Rational drug design

From decades, viral diseases including emerging and chronic viral infections are increasing worldwide health concern. Corona virus, SARS COV-2, is a new strain identified in 2019 caused Covid-19, in Wuhan, China has caused more than 5,304,772 infections and ~342,029 deaths worldwide over 203 countries, and the numbers are increasing exponentially from time to time. Since no specific treatment and diagnosis are available for COVID-19, discovery of new antiviral agents have become the most urgent need than in past, especially from natural sources. Hence, our present study is aimed to investigate bioactive molecules from Zingiber officinale (ginger) and Allium sativum (garlic) as potential SARS COV-2 main protease inhibitors, using a molecular docking by Auto dock 4.2, with the Lamarckian Genetic Algorithm, to analyze the probability of docking. SARS COV-2 main protease was docked with five selected compounds (zingerone, gingerol, paradol, dichloro flavin (ginger), and allicin (garlic), and were analyzed by Auto dock 4.2, PyMol version 1.7.4.5. Chloroquine and hydroxy chloroquine were used as standards for comparison. The binding energies obtained from the docking of Covid-19 main protease with biological ligand; zingerone, gingerol, paradol, dichloro flavin, and allicin were -5.31, -4.73, -5.51, -6.05, -3.74 kcal/mol, while, standard drugs such as hydroxy chloroquine and chloroquine possess binding energies of -4.88 and -5.25 kcal/mol respectively. It indicates that, zingerone, paradol and dichloloroflavan show more binding energy than chloroquine and hydroxy chloroquine, whereas, gingerol and allicin exhibited lesser binding energy. Comparing these five molecules, dichloroflavan and paradol from ginger shows highest affinity and binding sites for target protein.

Compliance is a business capability that organizations strive to obtain, since it is considered as a competitive advantage. In order for an organization to enforce com-pliance regulations to its business processes and the IT infrastructure supporting them, it is necessary to define compliance rules in a formal manner so that appropriate automa-tion may be effected. Compliance rules must be extracted from corresponding compli-ance documents produced externally or internally most commonly in the form of legis-lation or contracts. To this end, a comprehensive method should be followed, starting from document analysis, moving to the identification of important features and ultimate-ly the construction of compliance rules that may be automatically enforced to business processes. In order to depict compliance concepts and the relations between them, a conceptual meta-model is proposed in this paper. It aims to assist business analysts to extract compliance rules from compliance documents ...

Metabolomics, understood as the science that manages the study of compounds from the metabolism, is an essential tool for deciphering metabolic changes in disease. The experiments rely on the use of high-throughput analytical techniques such as liquid chromatography coupled to mass spectrometry (LC-ToF MS). This hyphenation has brought positive aspects such as higher sensitivity, specificity and the extension of the metabolome coverage in a single run. The analysis of a high number of samples in a single batch is currently not always feasible due to technical and practical issues (i.e., a drop of the MS signal) which result in the MS stopping during the experiment obtaining more than a single sample batch. In this situation, careful data treatment is required to enable an accurate joint analysis of multi-batch data sets. This paper summarizes the analytical strategies in large-scale metabolomic experiments; special attention has been given to QC preparation troubleshooting and data ...

are 16-membered macrolide antibiotics produced by Micromonospora griseorubida sp. nov., and possess strong antibacterial activity against Gram-positive bacteria^. On the basis of degradative and spectroscopic ex-periments2"^, the structures of mycinamicins

G-rich sequences can fold into a four-stranded structure called a G-quadruplex, and sequences with short loops are able to aggregate to form stable quadruplex multimers. Few studies have characterized the properties of this variety of quadruplex multimers. Using molecular modeling and molecular dynamics simulations, the present study investigated a dimeric G-quadruplex structure formed from a simple sequence of d(GGGTGGGTGGGTGGGT) (G1), and its interactions with a planar ligand of a perylene derivative (Tel03). A series of analytical methods, including free energy calculations and principal components analysis (PCA), was used. The results show that a dimer structure with stacked parallel monomer structures is maintained well during the entire simulation. Tel03 can bind to the dimer efficiently through end stacking, and the binding mode of the ligand stacked with the 3′-terminal thymine base is most favorable. PCA showed that the dominant motions in the free dimer occur on the loop regions, and the presence of the ligand reduces the flexibility of the loops. Our investigation will assist in understanding the geometric structure of stacked G-quadruplex multimers and may be helpful as a platform for rational drug design.

Abstract⎯We have previously described nanocomposites containing conjugates or complexes of native oligodeoxyribonucleotides with poly-L-lysine and TiO 2 nanoparticles. We have shown that these nanocomposites efficiently suppressed influenza A virus reproduction in MDCK cells. Here, we have synthesized previously undescribed nanocomposites that consist of TiO 2 nanoparticles and polylysine conjugates with oligonucleotides that contain phosphoryl guanidine or phosphorothioate internucleotide groups. These nanocomposites have been shown to exhibit antiviral activity in MDCK cells infected with H5N1 influenza A virus. The nanocomposites containing phosphorothioate oligonucleotides inhibited virus replication ~130-fold. More potent inhibition, i.e., ~5000-fold or ~4600-fold, has been demonstrated by nanocomposites that contain phosphoryl guanidine or phosphodiester oligonucleotides, respectively. Free oligonucleotides have been nearly inactive. The antiviral activity of oligonucleotides of all three types, when delivered by Lipofectamine, has been significantly lower compared to the oligonucleotides delivered in the nanocomposites. In the former case, the phosphoryl guanidine oligonucleotide has appeared to be the most efficient; it has inhibited the virus replication by a factor of 400. The results make it possible to consider phosphoryl guanidine oligonucleotides, along with other oligonucleotide derivatives, as potential antiviral agents against H5N1 avian flu virus.

The present work was designed to evaluate the toxicity of various synthesized aromatic amides that are analogs of N,N-diethyl-2-phenylacetamide, a well known insect repellent. The toxicity proÞle of these compounds was compared with N,N-diethyl-2-phenylacetamide as well as other registered insect repellents namely N,N-diethyl-3-methyl benzamide and N,N-diethylbenzamide. The primary skin irritation index values of the compounds, dermal toxicity of the chemicals and acute oral toxicity data to assess the safety of the synthesized aromatic amides are reported in this paper. Results of hematological and biochemical studies of these analogues are reported and discussed.

O-linked-N-acetyl glucosaminetransferase (OGT) is an important enzyme which regulates many important cellular processes through posttranscriptional modification of the nuclear and cytosolic proteins. OGT catalyzes the attachment of N-acetylglucosamine portion of uridine diphosphate Nacetyl glucosamine (UDP-GlcNac) to the serine and threonine residues of nuclear and cytoplasmic proteins of multicellular eukaryote in protein O-GlcNacylation process. Hyperglycemia increases GlcNacylation of proteins. GlcNacylation has been linked to some human diseases, such as cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, and cancer. Several inhibitors of the enzyme have been explored in the treatment of the diseases associated with it. In

Coronavirus disease (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). Although many vaccines have been developed against the virus, problems associated with vaccine resistance, vaccine apathy and the evolution of variants of the virus with increased transmissibility calls for the development of more effective and affordable drugs to combat the disease. Natural source drugs are regarded as an essential part of the therapy regimen for COVID-19 treatment and other viral respiratory infections as such needs to be exploited for the treatment of the virus globally. The study aimed to computationally screen the phytochemicals of some Nigerian plants used in the therapy of common cold for anti-COVID-19 activity. Phytochemical analysis of the plant extracts was performed employing standard techniques, while Gas chromatography-mass spectrometry was used to detect the bioactive compounds present in the extracts. The selected plant bioactive compounds were docked against the SARS-CoV-2 Main protease (M pro ), RNA-dependent RNA polymerase (RdRp), and S protein-ACE2 targets, while Lopinavir, Remdesivir and Favipiravir were included as standard ligands. The phytochemical constituents of the extracts were steroids, flavonoids, saponins, tannins, phenols, glycosides, terpenoids, and alkaloids. All the bioactive compounds exhibited acceptable drug-likeness and good oral bioavailability prediction, in addition to 89% of the compounds having slightly or practically non-oral toxicity using SwissADME and ProTox-II prediction servers. The overall result suggested that 3-Epimoretenol, Beta-Amyrin acetate, Methyl 3-oxours-12-en-23-oate, 20(29)-Lupenol acetate and Lanosterol acetate are the top most promising therapeutic bioactive natural compounds with antiviral activity against the SARS-CoV-2 Mpro, RdRp and spike protein when compared to standard drugs. Taken together, data obtained reveal that these bioactive natural compounds may have a very good potential as anti-COVID-19 therapy. COVID-19 • Remdesivir • RNA-Dependent RNA polymerase • SARS-CoV-2 • Main protease • Phytochemicals * Nkechi Eucharia Egbe

Rational Drug Design (RDD) has changed the way drugs are discovered over the past twenty years, serving as a key driver in the global pharmaceutical and healthcare industry revolution. By leveraging advances in bioinformatics, protein structure, cloud computing, and artificial intelligence, RDD enables the discovery and optimization of drug molecules with high accuracy, speed, and efficiency. This method not only accelerates drug discovery and reduces research costs, but also opens up possibilities for more personalized therapies that were previously unimaginable. Through a systematic analysis of ten peer-reviewed journals from 2015 to 2025, this paper explores the influence of RDD on research efficiency, success in clinical trials, and future challenges and opportunities. Quantitative and qualitative data from the selected studies were analyzed meta-thematically and presented in tables and graphs to support the arguments proposed. The findings of the analysis show that RDD consistently shortens drug development time by up to 40%, increases the chances of drug candidate success in the early phases of clinical trials, and expands the range of precision therapies for cancer, infection, and neurodegenerative diseases. Nonetheless, issues regarding biological validation, big data, and ethics in AI remain important challenges that need to be addressed. The paper concludes by stating that continued investment in RDD, cross-disciplinary integration, and improved regulation will be key to designing a more effective, safe, and inclusive healthcare system in the future.

Determining the structure and function of a novel protein is a cornerstone of many aspects of modern biology. For this study, the structure of a unique enzyme from Anoxybacillus sp. SK3-4 was predicted and identified based on its primary sequence analysis in which various computational tools were used. The structure was predicted to be identified as Oxidoreductase which belongs to alcohol dehydrogenase (ADH) family or iron-containing alcohol dehydrogenase (Fe-ADH) super-family after when the sequence is being analysed by Uniprot databases in which a maximum identity similarity of 100% was obtained with organism Anoxybacillus sp. SK3-4. Characteristic features of the enzyme were also predicted by computing both physical and the chemical parameters of the primary sequence using ProtParam software in Expasy. Active-sites, conserved regions or domains, secondary structure, 3D-model and transmembrane were all predicted using different software programs. Cn3D and Jalview software were als...

Structural studies are part of a rational drug design program aimed at inhibiting the S100B-p53 interaction and restoring wild-type p53 function in malignant melanoma. To this end, structures of three compounds (SBi132, SBi1279, and SBi523) bound to Ca 2+ -S100B were determined by X-ray crystallography at 2.10 A ˚(R free = 0.257), 1.98 A ˚(R free = 0.281), and 1.90 A ˚(R free =0.228) resolution, respectively. Upon comparison, SBi132, SBi279, and SBi523 were found to bind in distinct locations and orientations within the hydrophobic target binding pocket of Ca 2+ -S100B with minimal structural changes observed for the protein upon complex formation with each compound. Specifically, SBi132 binds nearby residues in loop 2 (His-42, Phe-43, and Leu-44) and helix 4 (Phe-76, Met-79, Ile-80, Ala-83, Cys-84, Phe-87, and Phe-88), whereas SBi523 interacts with a separate site defined by residues within loop 2 (Ser-41, His-42, Phe-43, Leu-44, Glu-45, and Glu-46) and one residue on helix 4 (Phe-87). The SBi279 binding site on Ca 2+ -S100B overlaps the SBi132 and SBi523 sites and contacts residues in both loop 2 and helix 4 (Ile-80, . NMR data, including saturation transfer difference (STD) and 15 N backbone and 13 C side chain chemical shift perturbations, were consistent with the X-ray crystal structures and demonstrated the relevance of all three small molecule-S100B complexes in solution. The discovery that SBi132, SBi279, and SBi523 bind to proximal sites on Ca 2+ -S100B could be useful for the development of a new class of molecule(s) that interacts with one or more of these binding sites simultaneously, thereby yielding novel tight binding inhibitors specific for blocking protein-protein interactions involving S100B.

Combinatorial Chemistry is a powerful new technology in drug design and molecular recognition. It is a wetlaboratory methodology aimed at "massively parallel" screening of chemical compounds for the dkcovery of compounds that have a certain biological activity. The power of the method comes from the interaction between experimental design and computational modeling. Principles of "rational" drug design are used in the construction of combinatorial libraries to speed up the discovery of lead compounds with the desired biological activity. This paper presents algorithms, software development and computational complexity analysis for problems arising in the design of combinatorial libraries for drug discovery. We provide exact polynomial time algorithms and intractability results for several Inverse Problems -formulated as (chemical) graph reconstruction problems -related to the design of combinatorial libraries. These are the first rigorous algorithmic results in the literature. We also present results provided by our combinatorial chemistry software package OCOTILLO for combinatorial peptide design using real data libraries. The package provides exact solutions for general inverse problems based on shortest-path topological indices. Our results are superior both in accuracy and computing time to the best software reports published in the literature. For 5-peptoid design, the computation is rigorously reduced to an exahustive search of about 2% of the search space; the exact solutions are found in a few minutes.

Abbreviations used: 2 0 OmG, 2 0 -O-methylguanosine; 4E-BP1, 4E binding protein 1, also called phosphorylated heatand acid-stable protein regulated by insulin (PHAS-I); bz 7 GTP, 7-benzylguanosine 5 0 -triphosphate; eIF4E, eukaryotic initiation factor 4E; eIF4G, eukaryotic initiation factor 4G, also called p220 or eIF4g; et 7 GTP, 7-ethylguanosine 5 0 -triphosphate; m 2 2,7 GTP, N 2 ,7-dimethylguanosine 5 0 -triphosphate; m 3 2,2,7 GTP, N 2 ,N 2 ,7-trimethylguanosine 5 0 -triphosphate; m 7 G, 7-methylguanosine; m 7 GDP, 7-methylguanosine 5 0 -diphosphate; m 7 GMP, 7-methylguanosine 5 0 -monophosphate; m 7 GpppG, P 1 -7-methylguanosine-5 0 P 3 -guanosine-5 0 triphosphate and similarly other dinucleoside triphosphates and tetraphosphates; m 7 GTP, 7-methylguanosine 5 0 -triphosphate; p, PO 3 2 ; p-Cl-bz 7 GTP, 7-( pchlorobenzyl)-guanosine 5 0 -triphosphate; TST, time-synchronized titration.

Human epidermal growth factor receptor or HER2 is a key player in breast, ovarian, and gastric cancers. Mutations that cause HER2 overexpression may alter their binding properties and sensitivity towards certain drugs. This study investigates the sequential amino acid interactions of extracellular HER2 receptors with antibodies and intracellular HER2 receptors with chemical inhibitor ligands using Molecular Docking to obtain the best drug model with the greatest binding affinity to the HER2 receptor. Additionally, analysis of the HER2 protein-protein interactions, degradation mechanism, stability analysis, Lipinski's Rule of Five, ADMET profiling of the inhibitors was done. The molecular docking of extracellular HER2 receptor and antibodies Trastuzumab and Pertuzumab showed higher binding affinity for the improved Trastuzumab. Molecular docking of intracellular HER2 receptor and 12 inhibitor ligands showed that the binding affinity of the plant-based inhibitor was not higher than the control inhibitor, SYR127063. However, the opposite goes for the approved inhibitors Tucatinib and Lapatinib, as it gives a higher binding affinity than control. According to Lipinski's Rule of Five, ADMET profile and molecular docking results, the best-approved inhibitors and plant-based inhibitors were Lapatinib and Sanguinarine, respectively. Although Lapatinib's MW exceeds 500 g/mol, violating Lipinski's drug likeness parameter, and Sanguinarine's protein-ligand stability analysis proved unstable, while Dacomitinib is the most stable. The results provided information on the binding properties of HER2 receptors with various inhibitors, which could be useful for future research on potential anti-cancer drugs to target and degrade HER2 receptors with optimal binding affinity. Furthermore, in-vitro cell-based assay studies are required to test the efficacy of the plant-based inhibitors toward HER2 receptor and cellular safety.

Over the past year there have been some interesting and significant advances in computer-based ligand-protein docking techniques and related rational drug-design tools, including flexible ligand docking and better estimation of binding free energies and solvation energies. As a result, the successful use of computational tools to help generate interesting new guide (lead) compounds for targeted receptors is becoming more commonplace.

Introduction: In sickle cell anemia, deoxygenated HbS molecules polymerize into long fibers in deep tissues during hypoxia, leading to erythrocyte sickling and capillary and vessel blockage. We are searching for new ligands, such as gbt440, that can inhibit HbS polymerization. Methods and Materials: We obtained the molecular model of hemoglobin [PDB ID: 1NEJ] from the Protein Data Bank and the molecular models of GBT440 and curcumin from the PubChem database. The physicochemical properties were investigated using SwissADME software, followed by docking to identify protein-ligand binding sites and determine their affinity. Finally, molecular dynamics simulations were conducted to assess the stability of the protein-ligand complex in the alpha-cleft of the hemoglobin tetramer model [PDB ID: 1NEJ]. Results and Discussion: The docking results revealed that curcumin exhibited a higher binding affinity than GBT440 to the nearby binding site of gbt440 in the alpha-cleft of the hemoglobin model. The hydrogen bonding and electrostatic interactions of the 1NEJ-GBT440 complex differed from those of the 1NEJ-curcumin complex. The results of the molecular dynamics simulation showed no significant difference in the flexibility of hemoglobin among the different ligand-hemoglobin complexes. Conclusion: The binding of curcumin to hemoglobin in the alpha cleft may inhibit the transition of hemoglobin to the tense state and stabilize the hemoglobin tetramer model [PDB ID: 1NEJ] in the R2 state. However, further investigation in the laboratory is necessary to confirm this.

Background: Schistosomes cause more mortality and morbidity than any other human helminth, but control primarily relies on a single drug that kills adult worms. The newly transformed schistosomulum stage is susceptible to the immune response and is a target for vaccine development and rational drug design. Methodology/Principal Findings: To identify genes which are up-regulated during the maturation of Schistosoma mansoni schistosomula in vitro, we cultured newly transformed parasites for 3 h or 5 days with and without erythrocytes and compared their transcriptional profiles using cDNA microarrays. The most apparent changes were in the up-regulation of genes between 3 h and 5 day schistosomula involved in blood feeding, tegument and cytoskeletal development, cell adhesion, and stress responses. The most highly up-regulated genes included a tegument tetraspanin Sm-tsp-3 (1,600-fold up-regulation), a protein kinase, a novel serine protease and serine protease inhibitor, and intestinal proteases belonging to distinct mechanistic classes. The inclusion of erythrocytes in the culture medium resulted in a general but less pronounced increase in transcriptional activity, with the highest up-regulation of genes involved in iron metabolism, proteolysis, and transport of fatty acids and sugars. Conclusions: We have identified the genes that are up-regulated during the first 5 days of schistosomula development in vitro. Using a combination of gene silencing techniques and murine protection studies, some of these highly up-regulated transcripts can be targeted for future development of new vaccines and drugs.

Recent improvements in flexible docking technology may lead to a bigger role for computational methods in lead discovery. Although fast and accurate computational prediction of binding affinities for an arbitrary molecule is still beyond the limits of current methods, the docking and screening procedures can select small sets of likely lead candidates from large libraries of either commercially or synthetically available compounds.

Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.

Using searching techniques based on algorithms derived from graph theory, we have established a similarity between a 3-dimensional cluster of side chains implicated in drug binding in influenza sialidase and side chains involved in isocitrate binding in Escherichia coli isocitrate dehydrogenase. The possible implications of the use of such comparative methods in drug design are discussed.

Using searching techniques based on algorithms derived from graph theory, we have established a similarity between a 3‐dimensional cluster of side chains implicated in drug binding in influenza sialidase and side chains involved in isocitrate binding in Escherichia coli isocitrate dehydrogenase. The possible implications of the use of such comparative methods in drug design are discussed.

The ability to identify protein binding sites and to detect specific amino acid residues that contribute to the specificity and affinity of protein interactions has important implications for problems ranging from rational drug design to analysis of metabolic and signal transduction networks. Support vector machines (SVM) and related kernel methods offer an attractive approach to predicting protein binding sites. An appropriate choice of the kernel function is critical to the performance of SVM. Kernel functions offer a way to incorporate domain-specific knowledge into the classifier. We compare the performance of three types of kernels functions: identity kernel, sequence-alignment kernel, and amino acid substitution matrix kernel in the case of SVM classifiers for predicting proteinprotein, protein-DNA and protein-RNA binding sites. The results show that the identity kernel is quite effective in on all three tasks. The substitution kernel based on amino acid substitution matrices that take into account structural or evolutionary conservation or physicochemical properties of amino acids yields modest improvement.

SOLID PHASE ORGANIC SYNTHESIS (SPOS) TO ACETOACETIC ESTER CHEMICAL FUNCIONALIZATION. The solid phase organic chemistry (SPOS) presented in this paper provides a pathway for a detailed study of lactones using acetoacetic ester as starting material. This emergent methodology allows a more diverse range of reactions to be carried out while retaining the advantages of purification step. In fact, the greatest advantage of SPOS is that the insoluble polymer attached to a starting material resumes the purification process in a single sequence of filtration an washing. This work investigated this methodology for the synthesis of 6-member lactones using Merriefield resin as polymeric support and the intermediate compounds were characterized by FT-IR-spectroscopy.

The following experimental techniques were used to determine the structure: The reported resolution of this entry is 2.05 Å. Percentile scores (ranging between 0-100) for global validation metrics of the entry are shown in the following graphic. The table shows the number of entries on which the scores are based. Whole archive (#Entries) Similar resolution (#Entries, resolution range(Å)) R f ree 130704 1692 (2.04-2.04) Clashscore 141614 1773 (2.04-2.04) Ramachandran outliers 138981 1752 (2.04-2.04) Sidechain outliers 138945 1752 (2.04-2.04) RSRZ outliers 127900 1672 (2.04-2.04)

In this paper, we designed, synthesized and tested a small set of three new derivatives potentially targeting the D3R-nAChR heteromer, a receptor complex recently identified and characterized as the molecular entity that, in dopaminergic neurons, mediates the neurotrophic effects of nicotine. By means of a partially rigidified spacer of variable length, we incorporated in the new compounds (1a-c) the pharmacophoric substructure of a known β2-subunitcontaining nAChR agonist (A-84543) and that of the D2/D3R agonist drug ropinirole. All the compounds retained the ability to bind with high affinity both β2-subunit-containing nAChR and D3R. Compound 1a, renamed HyNDA-1, which is characterized by the shortest linker moiety, was the most interesting ligand. We found, in fact, that HyNDA-1 significantly modulated structural plasticity on both mice and human dopaminergic neurons, an effect strongly prevented by co-incubating this ligand with either nAChR or D3R antagonists. Moreover, the neurotrophic effects of HyNDA-1 were specifically lost by disrupting the complex with specific interfering peptides. Interestingly, by using the Bioluminescence Resonance Energy Transfer 2 (BRET 2) assay in HEK-293 transfected cells, we also found that HyNDA-1 has the ability to increase the affinity of interaction between nAChR and D3R. Overall, our results indicate that the neurotrophic effects of HyNDA-1 are mediated by activation of the D3R-nAChR heteromeric complex specifically expressed on dopaminergic neurons.

The implementation of a novel sequential computational approach that can be used effectively for virtual screening and identification of prospective ligands that bind to trypanothione reductase (TryR) is reported. The multistep strategy combines a ligand-based virtual screening for building an enriched library of small molecules with a docking protocol (AutoDock, X-Score) for screening against the TryR target. Compounds were ranked by an exhaustive conformational consensus scoring approach that employs a rank-by-rank strategy by combining both scoring functions. Analysis of the predicted ligand-protein interactions highlights the role of bulky quaternary amine moieties for binding affinity. The scaffold hopping (SHOP) process derived from this computational approach allowed the identification of several chemotypes, not previously reported as antiprotozoal agents, which includes dibenzothiepine, dibenzooxathiepine, dibenzodithiepine, and polycyclic cationic structures like thiaazatetracyclo-nonadecahexaen-3-ium. Assays measuring the inhibiting effect of these compounds on T. cruzi and T. brucei TryR confirm their potential for further rational optimization.

The main objective of our rational drug design is to predict the best novel shorter chain peptide leads for cardio protective effect from the designed set of templates with various descriptors such as Lipinski rules, molinspiration and swissdock. We built 200 candidate molecules (50 dipeptide,50tripeptide,50 tetrapeptide,50 pentapeptides)and these combination sets were passed through empirical Lipinski filters to assess drug like properties using various molecular descriptors namely molecular mass, hydrogen bond donors, hydrogen bond acceptors, log p(<0.05).The results of Lipinski filters have identified one dipeptide(Leu-Lys),three tripeptides(Ala-Cys-Pro,Gly-Met-Trp,Gly-Trp-Ile)and two tetrapeptides(Ala-Tyr-Phe-Phe,Ala-Cys-Pro-Pro)as potent cardio protective leads. Further ,the selected above 6 peptide leads were subjected to assess drug like properties using molinspiration to check molinspiration property engine,milogp,TPSA,natoms,MW,nviolatios,nrotb,volumerespectively.The results of molinspiration have identified 5 peptide leads with rejection of one tetrapeptide Ala-Tyr-Phe-Phe.In addition ,the same set of leads(5peptides)were subjected to docking with angiotensin converting enzyme target (ACE inhibition)andreceptor target (BETA adrenergic receptor).The calculation of full fitness energy obtained between drug and target receptor/enzyme have shown clearly that the tripeptide Ala-Cys-Pro was more potent with regard to enzyme target having full fitness energy (-538894 k.cal/mol) ,Gly-Trp-Ile was the most potent lead against Betaadrenergic receptor blockade having full fitness energy of (-231766 k.cal/mol).Moreover the dipeptide Leu-Lys and tripeptide Gly-Met-Trp are also identified as potential targets against both enzyme (ACE) and receptor (BETA-2adrenergic)targets having full fitness energy of (-543953 k.cal/mol) and (-540163 k.cal/mol) against ACE enzyme and (-239715 k.cal/mol) and (-233794 k.cal/mol) against β 2 adrenergic target respectively. So we identified 4 compounds Ala-Cys-Pro, Gly-Trp-Ile, Leu-Lys, Gly-Met-Trp as potent peptide leads with maximum conformational stability for cardioprotective effect among the 200 peptide templates.

Withaniasomnifera, a well-known traditional medicinal plant, has garnered significant attention for its potential therapeutic applications. This study aims to investigate the binding interactions between selected Withania-derived phytochemicals and the CCR5 chemokine receptor, a crucial co-receptor for HIV-1 viral entry, through molecular docking simulations.The 3D crystal structure of the CCR5 receptor (PDB: 4MBS) was obtained, and the AutoDock 4.2.6 software was used for the molecular docking experiments. Two Withania compounds, 4-deoxywithaperuvin and 14-alpha,17-betadihydroxy-withanolide, were selected based on literature review and docked against the CCR5 receptor, along with the standard drug maraviroc.The docking results revealed that the Withaniaderived compounds exhibited favorable binding interactions with the CCR5 receptor, with binding energies comparable to or better than the standard drug. The in-silico analysis provided insights into the key residues and binding modes involved in the ligand-receptor interactions.This study suggests the potential of Withania-derived phytochemicals as promising lead compounds for the development of CCR5-targeted therapeutics against HIV-1 infection. Further experimental validation is warranted to corroborate these computational findings.

Withaniasomnifera, a well-known traditional medicinal plant, has garnered significant attention for its potential therapeutic applications. This study aims to investigate the binding interactions between selected Withania-derived phytochemicals and the CCR5 chemokine receptor, a crucial co-receptor for HIV-1 viral entry, through molecular docking simulations.The 3D crystal structure of the CCR5 receptor (PDB: 4MBS) was obtained, and the AutoDock 4.2.6 software was used for the molecular docking experiments. Two Withania compounds, 4-deoxywithaperuvin and 14-alpha,17-betadihydroxy-withanolide, were selected based on literature review and docked against the CCR5 receptor, along with the standard drug maraviroc.The docking results revealed that the Withaniaderived compounds exhibited favorable binding interactions with the CCR5 receptor, with binding energies comparable to or better than the standard drug. The in-silico analysis provided insights into the key residues and binding modes involved in the ligand-receptor interactions.This study suggests the potential of Withania-derived phytochemicals as promising lead compounds for the development of CCR5-targeted therapeutics against HIV-1 infection. Further experimental validation is warranted to corroborate these computational findings.

At the molecular level, most biological processes entail protein associations which in turn rely on a small fraction of interfacial residues called hot spots. Here we show that hot spots share a unifying molecular attribute: they provide a third-body contribution to intermolecular cooperativity. Such motif, based on the wrapping of interfacial electrostatic interactions, is essential to maintain the integrity of the interface and can be exploited in rational drug design since such regions may serve as blueprints to engineer small molecules disruptive of protein-protein interfaces.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socioeconomic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine-and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi-enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD.

In this paper, we designed, synthesized and tested a small set of three new derivatives potentially targeting the D3R-nAChR heteromer, a receptor complex recently identified and characterized as the molecular entity that, in dopaminergic neurons, mediates the neurotrophic effects of nicotine. By means of a partially rigidified spacer of variable length, we incorporated in the new compounds (1a-c) the pharmacophoric substructure of a known β2-subunitcontaining nAChR agonist (A-84543) and that of the D2/D3R agonist drug ropinirole. All the compounds retained the ability to bind with high affinity both β2-subunit-containing nAChR and D3R. Compound 1a, renamed HyNDA-1, which is characterized by the shortest linker moiety, was the most interesting ligand. We found, in fact, that HyNDA-1 significantly modulated structural plasticity on both mice and human dopaminergic neurons, an effect strongly prevented by co-incubating this ligand with either nAChR or D3R antagonists. Moreover, the neurotrophic effects of HyNDA-1 were specifically lost by disrupting the complex with specific interfering peptides. Interestingly, by using the Bioluminescence Resonance Energy Transfer 2 (BRET 2) assay in HEK-293 transfected cells, we also found that HyNDA-1 has the ability to increase the affinity of interaction between nAChR and D3R. Overall, our results indicate that the neurotrophic effects of HyNDA-1 are mediated by activation of the D3R-nAChR heteromeric complex specifically expressed on dopaminergic neurons.

Alzheimer&#39;s disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (Aβ). We have hypothesized that the intrinsic Aβ calcium channel activity of the oligomeric Aβ polymer may be responsible for the neurotoxic properties of Aβ, and that Aβ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the Aβ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the Aβ channel and protect neurons from Aβ toxicity. Both block the Aβ channel with similar potency (≈500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer&#39;s disease drug discovery.

A new class of 2-oxo-tetrahydro-1,8-naphthyridine-based protein farnesyltransferase inhibitors were synthesized and found to inhibit protein farnesyl transferase from the malaria parasite with potencies in the low nanomolar range. The compounds were much less potent on mammalian protein prenyltransferases. Two of the compounds block the growth of malaria growth in culture with potencies in the sub-micromolar range. Some of the compounds also were found to be much more metabolically stable than previously described tetrahydroquinoline-based protein farnesyltransferase inhibitors. Keywords malaria; P. falciparum; anti-malarials; protein farnesyltransferase; drug discovery Malaria remains one of the key parasitic diseases present today with more than 400 million acute illnesses and at least 2-3 million deaths annually throughout the tropical and subtropical regions of the world. The malaria parasite is able to become resistant to chemotherapeutic agents. For example, in many places there is a major problem of resistance to chloroquine, a 4-aminoquinoline that has been the mainstay of treatment for malaria for many years. Hence, there is urgent need for the development of new drugs against new molecular targets 1. Protein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Protein farnesyltransferase (PFT) transfers the farnesyl group from farnesyl diphosphate to the SH of the cysteine near the C-terminus of proteins such as Ras. PFT inhibitors (PFTIs) have been extensively developed as anti-cancer agents because

Based on rational drug design approach, a series of novel thiazolidin-4-ones bearing different aryl/heteroaryl moieties at position C-2 and N-3 are synthesized and evaluated as potent inhibitors for human immunodeficiency virus type-1 reverse transcriptase enzyme (HIV-1 RT). An in vitro HIV-1 RT assay showed that the compounds 4, 5, 6, 8, 12, 13, 14 and 17 have shown high inhibition of reverse transcriptase (75.41, 95.50, 98.07, 91.24, 85.27, 77.59, 84.11 & 76.49% inhibition) enzyme activity. Further, cell based assay showed that compounds 4, 5, 8 & 12 are identified as the best compounds of the series (EC 50 ranged from 0.09 to 0.8 lg/ml and 0.12 to 1.06 lg/ml) against HIV-1 III B and HIV-1 ADA5 strains, respectively. Moreover, the compounds which were active against HIV-1 III B and HIV-1 ADA5 were also found to be active against primary isolates (EC 50 ranged from 0.10 to 1.55 lg/ml against HIV-1 UG070 and 0.07 to 1.1 lg/ml against HIV-1 VB59), respectively. Structure-activity relationship (SAR) studies demonstrated the importance of the lipophilic bulky substituent pattern on compact heteroaryl ring at N-3, replacement of C4 0 at C-2 phenyl by trivalent bioisosteric nitrogen and dihalo groups at C-2 aryl/heteroaryl of thiazolidin-4-ones is crucial for anti-HIV-1 activity. Molecular modeling of compounds 4, 5, 8 and 12 in complex with HIV-1 RT demonstrate that there is good correlation of results obtained from SAR studies. Therefore the compounds 4, 5, 8 and 12 may be considered as good candidates for further optimization of anti-HIV-1 activity.

A set of semi-rigid cyclic and acyclic bis-quaternary ammonium analogs, which were part of a drug discovery program aimed at identifying antagonists at neuronal nicotinic acetylcholine receptors, were investigated to determine structural requirements for affinity at the blood-brain barrier choline transporter (BBB CHT). This transporter may have utility as a drug delivery vector for cationic molecules to access the central nervous system. In the current study, a virtual screening model was developed to aid in rational drug design/ADME of cationic nicotinic antagonists as BBB CHT ligands. Four 3D-QSAR comparative molecular field analysis (CoMFA) models were built which could predict the BBB CHT affinity for a test set with an r 2 < 0.5 and cross-validated q 2 of 0.60, suggesting good predictive capability for these models. These models will allow the rapid in silico screening of binding affinity at the BBB CHT of both known nicotinic receptor antagonists and virtual compound libraries with the goal of informing the design of brain bioavailable quaternary ammonium analogs that are high affinity selective nicotinic receptor antagonists.

The background and current context of work on the shikimate-pathway enzymes as potential targets for anti-bacterial, anti-fungal and anti-parasitic drugs is reviewed. Recent work on the third enzyme of the pathway, dehydroquinase, which occurs in two structurally and mechanistically distinct forms, is used to illustrate the present state of studies into rational drug design.

Drug resistance in Mycobacterium tuberculosis (M. tuberculosis) complicates management of tuberculosis. Efflux pumps contribute to low level resistance and acquisition of additional high level resistance mutations through sub-therapeutic concentrations of intracellular antimycobacterials. Various efflux pump inhibitors (EPIs) have been described for M. tuberculosis but little is known regarding the mechanism of efflux inhibition. As knowledge relating to the mechanism of action and drug target is central to the rational drug design of safe and sufficiently selective EPIs, this review aims to examine recent developments in the study of EPIs in M. tuberculosis from a rational drug development perspective and to provide an overview to facilitate systematic development of therapeutically effective EPIs. Review of literature points to a reduction in cellular energy or direct binding to the efflux pump as likely mechanisms for most EPIs described for M. tuberculosis. This review demonstrates that, where a direct interaction with efflux pumps is expected, both molecular structure and general physicochemical properties should be considered to accurately predict efflux pump substrates and inhibitors. Non-competitive EPIs do not necessarily demonstrate the same requirements as competitive inhibitors and it is therefore essential to differentiate between competitive and non-competitive inhibition to accurately determine structure activity relationships for efflux pump inhibition. It is also evident that there are various similarities between inhibitors of prokaryotic and eukaryotic efflux pumps but, depending on the specific chemical scaffolds under investigation, it may be possible to design EPIs that are less prone to inhibition of human P-glycoprotein, thereby reducing side effects and drug-drug interactions.

The activation of intracellular signaling pathways such as the classical nuclear factor kappaB (NF-kappaB) pathway is related to the pathogenesis of several inflammatory autoimmune diseases including rheumatoid arthritis (RA). To clarify the role of disease-relevant cell-types and signaling molecules in vitro or in vivo, it is necessary to target them selectively without disturbing the homeostasis of the immune system. We developed sneaking ligand fusion proteins (SLFPs) for cell-type specific modulation of signaling pathways. We designed the first SLFPs to inhibit the activation of NF-kappaB, a key regulator of inflammation, solely in the activated endothelium. Our "sneaking ligand" NF-kappaB inhibitor (named SLC1) inhibits NF-kappaB activation specifically in E-selectin expressing cells in vitro and in mouse models of arthritis indicating the importance of NF-kappaB in the activated endothelium. Clinical signs of arthritis were ameliorated by SLC1 treatment. We conclude that the SLFP architecture consisting of easily exchangeable domains represents an attractive approach to utilize other disease-relevant biological targets both on the cell surface and intracellularly. By relying on two independent disease specific targets, SLFPs may increase the therapeutic efficacy and reduce adverse effects.

Bacterium Mycobacterium tuberculosis is the causative agent for the disease tuberculosis (TB) and is responsible for more than ten million different infections with an additional accountability for about two million deaths every year. PT70 molecule as described in the literature acts as a drug in the market, which has been utilized as a curative agent for the disease. However, for these commercialized anti-tuberculotic drugs the causative agent that is Mycobacterium tuberculosis is becoming drug resistant in a progressive manner. Therefore, to combat the metabolic activity of the bacteria there is a need for a potent drug that could be subjected to cure TB. The present study deals with the perspective of designing a novel inhibitor as an anti-tuberculotic agent for which PT70 has been taken as a base molecule, which is henceforth used in molecular docking with the target INHA gene, and as a result, the process observed a binding energy as-10.133. Comparative molecules were selected based on the process of pharmacophore modeling which were then docked with the receptor molecule. On concluding remarks, top five molecules were prioritized on the bases of their binding energy (highest as-10.881) as compared to the PT70 molecule. Therefore, all such molecules selected will be taken as drug like molecules in future, which can be used for inhibiting the INHA gene. The aforementioned five molecules passed that ADMET analysis, membrane permeability test, pKa, and density function theory.