Papers by suman MANANDHAR
Advanced Pharmaceutical Bulletin
Glycogen synthase kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wi... more Glycogen synthase kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3β, serving as a central switch in the signaling pathways. Dysregulation of GSK-3β kinase has been reported in diabetes, cancer, Alzheimer’s disease, schizophrenia, bipolar disorder, inflammation, and Huntington’s disease. Thus, GSK-3β is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer’s disease, an age-related neurodegenerative brain disorder. GSK-3β activation increases amyloid-beta (Aβ) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3β are explored, and different existing classes of GSK-3β inhibitor...
AAPS PharmSciTech, Mar 22, 2024
Oral submucous fibrosis (OSF) is a chronic progressive disease associated with increased collagen... more Oral submucous fibrosis (OSF) is a chronic progressive disease associated with increased collagen deposition and TGF-β1 release. The current therapy and management have been a limited success due to low efficacy and adverse drug reactions. This study aimed to evaluate epigallocatechin 3-gallate (EGCG) encapsulated nanoparticles loaded mucoadhesive hydrogel nanocomposite (HNC) for OSF. Developed HNC formulations were evaluated for their permeation behaviour using in vitro as well as ex vivo studies, followed by evaluation of efficacy and safety by in vivo studies using areca nut extract-induced OSF in rats. The disease condition in OSF-induced rats was assessed by mouth-opening and biochemical markers. The optimized polymeric nanoparticles exhibited the required particle size (162.93 ± 13.81 nm), positive zeta potential (22.50 ± 2.94 mV) with better mucoadhesive strength (0.40 ± 0.002 N), and faster permeation due to interactions of the positively charged surface with the negatively charged buccal mucosal membrane. HNC significantly improved disease conditions by reducing TGF-β1 and collagen concentration without showing toxicity and reverting the fibroid buccal mucosa to normal. Hence, the optimized formulation can be further tested to develop a clinically alternate therapeutic strategy for OSF. Keywords ex vivo permeation and retention • epigallocatechin 3-gallate • in vivo efficacy and safety studies • mucoadhesive hydrogel nanocomposite • oral submucous fibrosis
Structural Chemistry, Jun 21, 2022
Scientific insights gained from the severe acute respiratory syndrome (SARS) and middle east resp... more Scientific insights gained from the severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) outbreaks have been assisting scientists and researchers in the quest of antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses and influenza viruses both rely on the host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation. Recent studies report SARS-CoV-2 also uses TMPRSS2 to enter cells. In the current study, we employed structure-based virtual screening of 1,82,651 natural compounds downloaded from the zin database against the homology model of the TMPRSS2 protein, followed by a molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening yielded 110 hits with docking scores ranging from -8.654 to -6.775 and glide energies ranging from -55.714 to -29.065 kcal/mol. The binding mode analysis revealed that the hit molecules made H-bond, Pi-Pi stacking and salt bridge contacts with the TMPRSS2 active site residues. MD simulations of the top two hits (ZINC000095912839 and ZINC000085597504) revealed to form a stable complex with TMPRSS2, with a minimal RMSD and RMSF fluctuation. Both the hit structures interacted strongly with the Asp180, Gln183, Gly184, Ser186, Gly207 and Gly209, as predicted by Glide XP docking, and formed a significant H-bond interaction with Ser181 in MD simulation. Among these two, ZINC000095912839 was having the most stable binding interaction with TMPRSS2 of the two molecules. The present study successfully identified TMPRSS2 ligands from a database of zinc natural molecules as potential leads for novel SARs-CoV-2 treatment.
Molecular Diversity
The Akt pathway plays a significant role in various diseases like Alzheimer’s, Parkinson’s, and D... more The Akt pathway plays a significant role in various diseases like Alzheimer’s, Parkinson’s, and Diabetes. Akt is the central protein whose phosphorylation controls many downstream pathways. Binding of small molecules to the PH domain of Akt facilitates its phosphorylation in the cytoplasm and upregulates the Akt pathway. In the current study, to identify Akt activators, ligand-based approaches like 2D QSAR, shape, and pharmacophore-based screening were used, followed by structure-based approaches such as docking, MM-GBSA, ADME prediction, and MD simulation. The top twenty-five molecules from the Asinex gold platinum database found to be active in most 2D QSAR models were used for shape and pharmacophore-based screening. Later docking was performed using the PH domain of Akt1 (PDB: 1UNQ), and 197105, 261126, 253878, 256085, and 123435 were selected based on docking score and interaction with key residues, which were druggable and formed a stable protein–ligand complex. MD simulations...
The Akt pathway plays an important role in cell metabolism, growth, proliferation, and survival. ... more The Akt pathway plays an important role in cell metabolism, growth, proliferation, and survival. Akt is the central protein whose phosphorylation controls many downstream pathways. In many diseases like Alzheimer’s, Parkinson, and diabetes, there is downregulation of the Akt pathway. It is proven that the binding of small molecules to the PH domain of Akt facilitates its phosphorylation in the cytoplasm. In the current study, to identify Akt activators, ligand-based approaches like fingerprint-based 2D-QSAR, shape, and pharmacophore-based screening were used, followed by structure-based approaches like docking, MM-GBSA, ADME prediction, and MD simulation. Using the 2D-QSAR activity of the Asinex gold platinum database was predicted, and the top twenty-five molecules found to be active using most models were selected for shape-based and pharmacophore-based screening. Later docking was performed using the PH domain of Akt1 (PDB: 1UNQ), and 197105, 261126, 253878, 256085, and 123435 we...
Journal of Cell Communication and Signaling
Introduction One of the most common problems of diabetes are diabetic foot ulcers (DFUs). Accordi... more Introduction One of the most common problems of diabetes are diabetic foot ulcers (DFUs). According to National Institute for Health, initial management of DFUs can decrease the complication of limb amputations and can improve the patient’s quality of life. DFU treatment can be optimized with the help of multidisciplinary approach. Based on many studies, control of glucose levels in blood, antioxidant activity, reduction in cytokine levels, re-epithelialization, collagen formation, migration of fibroblasts are major phases involved in managing DFU. Dehydrozingerone (DHZ), has been known for its anti-inflammatory, antioxidant and wound healing properties. Methodology Three months high-fat diet and low dose of streptozotocin-induced type-II diabetic foot ulcer model was used to evaluate the effectiveness of dehydrozingerone. DHZ was given orally to rats for 15 days post wounding. TNF-α, IL-1β and antioxidant parameters like lipid peroxidation, glutathione reductase were estimated. Imm...
蛋白質-チロシンホスファターゼ1Bの阻害剤としての潜在的天然化合物の仮想構造ベースドッキング,WaterMap及び分子動力学誘導同定【JST・京大機械翻訳】
Journal of Molecular Structure, 2021
BRAF gene as a potential target to attenuate drug resistance and treat cancer
Gene Reports
Effect of temperature on hematological and biochemical parameters when the biological sample from rats kept in room temperature, thermocol, polypropylene box and innovative portable refrigerator
This data was generated for the preclinical studies where biological samples from rats such as bl... more This data was generated for the preclinical studies where biological samples from rats such as blood, serum, liver were stored in different storage conditions such as room temperature, thermocol box, polypropylene box and in an innovative portable battery-operated re-chargeable refrigerator "Emvolio" developed by Blackfrog Technologies Private Limited, Manipal, India. The integrity of biochemical and hematological parameters are given, which indicates that Emvolio is maintaining a constant temperature for 10 hrs. The data also suggests that Emvolio can be effectively used in preclinical sample preservation and transportation. Emvolio is battery operated small, volume refrigerator for medicines, vaccines, food, beverages, dairy etc. and has Indian Patent (Patent number 201941013056; https://ipindiaservices.gov.in/publicsearch). These data also support its preclinical uses in laboratories where animal test samples can be preserved and transported.
Protective Effects of Gossypin in Colchicine-induced Cognitive Dysfunction and Oxidative Damage in Rats
Research Journal of Pharmacy and Technology, 2020
Alzheimer’s disease (AD) is associated with cognitive deficits and epigenetic deacetylation that ... more Alzheimer’s disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-betacyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking, and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2) inhibition. We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC a...
Indian Journal of Pharmaceutical Education and Research, 2021
Purpose: Alzheimer's is a disease affecting mostly the Older population leading to the deteriorat... more Purpose: Alzheimer's is a disease affecting mostly the Older population leading to the deterioration of cognitive capabilities. The protective effect of Caffeic acid in Colchicineinduced dementia was evaluated in the current study. Materials and Methods: Colchicine was administered intracerebroventricularly (ICV) to the lateral ventricle of the brain (at the coordinates 0.8 mm posterior to bregma, 1.8 mm lateral to the sagittal suture, 3.6 mm below the cortical surface) using robotic stereotaxic apparatus that results in Alzheimer's type sporadic dementia. Caffeic acid at the dose of 50 mg/kg p.o, was administered daily for 25 days starting four days before the colchicine injection and evaluated for its neuroprotective activity. The spatial memory of animals was evaluated using Morris water maze followed by biochemical estimations of acetylcholinesterase and antioxidant markers in the hippocampal and frontal cortex region of the brain. Results: Intracerebroventricular injection of colchicine in rat brain resulted in decreased cognitive abilities as evident in escape latency and average speed of the retention trial. Significant changes in the escape latency were noted in Caffeic acid-treated group. The level of acetylcholinesterase and antioxidant markers like glutathione, catalase, lipid peroxidation, superoxide dismutase were significantly changed in the hippocampal region of the rats but not in the frontal cortex region in the caffeic acid treatment groups. Conclusion: The current study provides evidence for the neuroprotective and antioxidative potential of caffeic acid in intracerebroventricularly injected Colchicine-induced sporadic model of AD.
Journal of Molecular Structure, 2021
Neuroinflammation is considered as the pathological hallmark of neurodegenerative diseases, inclu... more Neuroinflammation is considered as the pathological hallmark of neurodegenerative diseases, including Alzheimer's disease (AD). Under inflammatory conditions, activation of microglial cells results in the increased expression of Protein tyrosine phosphatase 1B (PTP1B) levels, enhancing pro-inflammatory response. Computation based i n silico docking studies were done using maestro interface to identify the inhibitors of PTP1B. A library of 1941 phytomolecules from Zinc database was screened for evaluation of their binding potential with PTP1B. Phytomolecules with better activity and binding were shortlisted after HTVS, SP, and XP mode of docking. The refining of the hit molecules was done by the analysis of the pharmacokinetic properties and toxicity prediction using QikProp tool. The molecules with better binding and pharmacokinetic properties were selected for WaterMap analysis and Molecular dynamics simulation study. The top three compounds were selected for further studies, including QikProp analysis, water map analysis, and molecular dynamics study. Compounds ZINC0 0 0 0 01785780, ZINC0 0 0 013543704, ZINC0 0 0 040874044 were found to be potent inhibitors against PTP1B based on the docking score and binding interactions. Among the selected molecules, ZINC0 0 0 013543704 showed better stability in the molecular dynamics simulation study and WaterMap study. The identified hit could be a potent inhibitor of PTP1B that further requires experimental validation using in vitro and in vivo experimental models.
Molecular Diversity
Breast cancer is a common form of cancer that affects both men and women. One of the most common ... more Breast cancer is a common form of cancer that affects both men and women. One of the most common types of genomic flaws in cancer is the aberrations in the PI3K/AKT/mTOR pathway. The benefit of dual targeting PI3K as well as mTOR is that the kinase-positive feedback loops are more effectively inhibited. Therefore, in the current study, structure-based models like molecular docking, MM-GBSA, Qikprop, induced fit docking, simulated molecular dynamics (MD), and thermal MM-GBSA were used to identify the phytochemicals from the zinc 15 database, which may inhibit PI3K and mTOR. After docking the phytochemicals with PI3K (PDB 4FA6), ten ligands based on the docking score were selected, among which salvianolic acid C had the highest docking score. Hence, salvianolic acid A was also docked. All the ligands taken showed a binding energy of greater than − 30 kcal/mol. The predicted ADME showed that the ligands have druggable properties. By performing MD of the top five ligands and salvianolic...
Structural Chemistry
Scientific insights gained from the severe acute respiratory syndrome (SARS) and middle east resp... more Scientific insights gained from the severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS) outbreaks have been assisting scientists and researchers in the quest of antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses and influenza viruses both rely on the host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation. Recent studies report SARS-CoV-2 also uses TMPRSS2 to enter cells. In the current study, we employed structure-based virtual screening of 1,82,651 natural compounds downloaded from the zin database against the homology model of the TMPRSS2 protein, followed by a molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening yielded 110 hits with docking scores ranging from −8.654 to −6.775 and glide energies ranging from −55.714 to −29.065 kcal/mol. The binding mode analysis revealed that the hit molecules made H-bond, Pi-Pi stacking and salt bridge contacts with the TMPRSS2 active site residues. MD simulations of the top two hits (ZINC000095912839 and ZINC000085597504) revealed to form a stable complex with TMPRSS2, with a minimal RMSD and RMSF fluctuation. Both the hit structures interacted strongly with the Asp180, Gln183, Gly184, Ser186, Gly207 and Gly209, as predicted by Glide XP docking, and formed a significant H-bond interaction with Ser181 in MD simulation. Among these two, ZINC000095912839 was having the most stable binding interaction with TMPRSS2 of the two molecules. The present study successfully identified TMPRSS2 ligands from a database of zinc natural molecules as potential leads for novel SARs-CoV-2 treatment.
Emvolio Study - The ARRIVE guidelines 2.0 - Author checklist.pdf
The file contains the ARRIVE2.0 Author Checklist for experiments carried out using rats.
Structural Chemistry, 2022
The scientific insights gained from the severe acute respiratory syndrome (SARS) and the middle e... more The scientific insights gained from the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) outbreaks are helping scientists to fast-track the antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses, as well as influenza viruses, depend on host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation in the human cell. Recent studies show that SARS-CoV-2 also uses TMPRSS2 for its cell entry. In the present study, a structure-based virtual screening of 52,337, protease ligands downloaded from the Zinc database was carried out against the homology model of TMPRSS2 protein followed by the molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening has identified 13 hits with a docking score range of −10.447 to −9.863 and glide energy range of −60.737 to −40.479 kcal/mol. The binding mode analysis shows that the hit molecules form H-bond (Asp180, Gly184 & Gly209), Pi-Pi stacking (His41), and salt bridge (Asp180) type of contacts with the active site residues of TMPRSS2. In the MD simulation of ZINC000013444414, ZINC000137976768, and ZINC000143375720 hits show that these molecules form a stable complex with TMPRSS2. The complex equilibrates well with a minimal RMSD and RMSF fluctuation. All three structures, as predicted in Glide XP docking, show a prominent interaction with the Asp180, Gly184, Gly209, and His41. Further, MD simulation also identifies a notable H-bond interaction with Ser181 for all three hits. Among these hits, ZINC000143375720 shows the most stable binding interaction with TMPRSS2. The present study is successful in identifying TMPRSS2 ligands from zinc data base for a possible application in the treatment of COVID-19.
F1000Research, 2022
Background: Emvolio is a non-medical device, indigenously developed portable refrigeration for ma... more Background: Emvolio is a non-medical device, indigenously developed portable refrigeration for maintaining the internal temperature 2–8˚C. The Indian Patent Office has granted patent for applications such as preservation and transport of medicines, vaccines, food, beverages, dairy etc. Further, use of Emvolio can be utilized in transport and store biologicals to preserve their biochemical and cellular integrity. The objective of this study was to evaluate the biochemical and haematological integrity of biological samples such as rat blood, serum and liver. Methods: The steady temperature was maintained inside the Emvolio, and it was compared to that of thermocol and polypropylene boxes aided with frozen gel packs. The blood and liver samples were isolated from Wistar rats and kept in Emvolio, thermocol and polypropylene boxes for 10 hrs, and the temperature was monitored. The blood parameters, namely red blood cells (RBC), white blood cells (WBC), platelets, haematocrit, haemoglobi...
Chemical Papers, 2021
Inclining mortality with a constant plummet in the survival rates associated with glioblastoma st... more Inclining mortality with a constant plummet in the survival rates associated with glioblastoma still stands as an inveterate predicament. The only promising therapy with temozolomide (TMZ) is now side-lined due to escalated resistance mediated by Poly (ADP-ribose) Polymerase-1 (PARP-1). In the light of this, the very study was designed to evaluate the potential of an active phyto component named naringin, in inhibiting PARP-1, using in silico and in vitro methods. Under in silico settings, inhibitor bound crystal structure of PARP-1, i.e., 4UND was retrieved and molecular docking studies were performed against naringin using Schrodinger software. In vitro cytotoxicity and apoptotic detection assay were performed using C6 glioma cells. Docking studies revealed high affinity and low binding energy at the inhibition site with good stability. An increase in cytotoxicity to C6 cells was observed with TMZ and naringin combination when compared to TMZ alone. Isobologram plot confirmed the ...
In Silico Evaluation of the Role of Phytochemicals in Alzheimer's Disease Through Wnt Signaling Modulation
Special Publications, 2019
Alzheimer’s disease (AD) is an irreversible, progressive and the most common reason for neurodege... more Alzheimer’s disease (AD) is an irreversible, progressive and the most common reason for neurodegenerative disease. Wnt signaling plays important role during embryonic CNS development and is involved in neuronal induction, self-renewal, polarity, and synaptogenesis. Alteration in the Wnt Signaling pathway has been linked with age-related diseases like osteoporosis, colon cancer, Parkinson and AD. Several studies indicate that disruption of Wnt signaling particularly, canonical Wnt pathway contributes to AD pathogenesis. This study aims to evaluate the role of phytochemical in modulating Wnt signaling pathway by targeting the negative regulators of Wnt signaling. WIF1 (Wnt inhibitory factor 1) is the protein that binds to Wnt proteins making them unavailable and hence inhibiting the Wnt signaling. Low density lipoprotein receptor related protein 6 (Lrp6) is the co-receptor that along with Frizzled receptor is involved in the activation of Wnt signaling. Dickkopf 1(Dkk1) is the antagon...
Uploads
Papers by suman MANANDHAR