Rohoullah Firouzi

Chemistry and Chemical Engineering Research Center of Iran, Physical Chemistry, Faculty Member

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I received a B.S. in Chemistry from the University of Tehran in 2001 and an M.S. and PhD in Physical Chemistry from Shahid Beheshti University in 2004 and 2009, respectively. I joined the Chemistry & Chemical Engineering Research Center of Iran, Tehran, in June of 2011.

Research Interests:

My research focuses on the use of computational and theoretical methods to tackle challenging problems in chemistry, biophysics, and structural biology.

- The use of high-throughput virtual screening techniques and chemical informatics platforms for structure-based drug discovery (SBDD).

- The use of molecular simulations techniques and statistical methods to study the structure, dynamics and interactions of (dis)ordered proteins at the atomic level.

- The use of linear-scaling electronic structure methods to provide a more realistic description of the physics of the protein-ligand binding interaction and to modify docking methods for scoring protein-ligand binding.

- The use of (computational) quantum chemistry to study the challenging chemical problems, such as the prediction of the reaction mechanisms, the analysis of non-covalent interactions in crystal structures, and the definition of some virtual quantities (like the chemical bond and aromaticity).

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Papers by Rohoullah Firouzi

Ab initio studies of BN-acenes and cyclo BN-acenes electronic properties and their dependence on the molecular size and the number of electrons

Journal of Molecular Structure-theochem, Jul 1, 2009

In this account, the energy properties (total electronic energy, zero point energy correction, th... more In this account, the energy properties (total electronic energy, zero point energy correction, thermal energy correction, the change in DH f 0 on going from 0 to 298 K, atomization energy, and frontier orbital energies), dipole polarizability, and several important bands in the UV spectra (p, a, and b bands) of linear and zigzag BN-acenes and their corresponding cyclic structures have been calculated at several levels of theory. Various correlations have been reported among these properties for BN-acenes and cyclo BNacenes versus the total number of electrons and the number of rings as well. It has been demonstrated that all studied molecular properties of these series, change linearly with the number of ring as well as the number of electrons, except for frontier molecular orbital energies and excitation energies between them (UV bands). The linear changes of these properties with the number of rings and the total number of electrons were used to generate fit equations. Extracting these equations makes it possible to estimate aforementioned properties for large homologues of the series which satisfy chemical accuracy, yet requiring much less computational work. Also, it has been found that, the quality of the linear equations (values of linear correlation coefficients) with respect to either the number of electrons or rings is insensitive to the combination of methods and basis sets employed to derive the mentioned molecular electronic properties.

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Polyacenes electronic properties and their dependence on molecular size

Journal of Molecular Structure-theochem, Aug 1, 2008

The closed shell singlet electronic energies, atomization energies, polarizabilities, rotational ... more The closed shell singlet electronic energies, atomization energies, polarizabilities, rotational constants and geometrical parameters of linear and angular (zigzag) polyacenes have been calculated employing HF and two DFT methods (B3LYP and LSDA) in conjunction with 6-31G(d) basis set. The possible linear and asymptotic relations of molecular properties of polyacene versus number of benzene rings as well as versus total number

A new chromium (III) complex containing N-(2-pyridylmethyl)-2-pyrazinecarboxamide, (NPyPzCa): Synthesis, molecular and crystal structure and theoretical electron density analysis

Solid State Sciences, Dec 1, 2010

The chromium (III) complex [Cr(NPyPzCa)Cl 2 (H 2 O)].(CH 3) 2 O (1) (NPyPzCa stands for N-(2-pyri... more The chromium (III) complex [Cr(NPyPzCa)Cl 2 (H 2 O)].(CH 3) 2 O (1) (NPyPzCa stands for N-(2-pyridylmethyl)-2-pyrazinecarboxamide) has been synthesized and characterized by single crystal X-ray diffraction. The Cr(III) atom exhibits an octahedral geometry due to the coordination of three donor atoms from carboxamide ligand, two chlorine atoms and one water molecule. There is OeH/O hydrogen bonds and also pep interactions between adjacent pyridine and pyrazine rings that seem to be effective in the stabilization of the crystal packing. The topological and energetic properties of the electron density distribution of all the metaleligand bonding interactions in this complex have also been calculated and studied at several DFT levels. According to the results, metaleligand bonding interactions belong (from the topological and energetic point of view) to new interactions that represent a mix of closed-shell (ionic) and shared (covalent) characters.

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Linear regression analysis of molecular energy properties for poly heterocyclic compounds

Journal of Molecular Structure-theochem, Jul 1, 2009

Energy properties (total electronic energies, kinetic energies, atomization energies, zero point ... more Energy properties (total electronic energies, kinetic energies, atomization energies, zero point energies, thermal energies, and thermal enthalpies) of several linear homologous of poly heterocyclic compounds have been calculated using HF and B3LYP in conjunction with 6-31G(d) basis set. Calculated energy properties of each family of homologous series have been employed to generate a fit function versus the total number of electrons as well as the number of repeating units. The observed perfect linearity of regression lines of every homologous compound can be used to predict estimated energy properties of homologous from the regression parameters determined for a set of known energy properties of smaller compounds which belong to the same homologous series. From these values, extrapolated energy properties of even large molecules are accessible within chemical accuracy. Also, it has been found that, except for absolute values, the trends of various energy properties remain the same, at two levels of calculation. The success of the linear fittings with respect to either the number of electrons or the number of repeating units is insensitive to the inclusion of electron correlation.

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Conclusive evidence on the insensitivity of additive rules to the combinational details of exchange and correlation functional in hybrid DFT methods

International Journal of Quantum Chemistry, 2009

This account is a quest to evaluate the sensitivity of additive rules among total electronic ener... more This account is a quest to evaluate the sensitivity of additive rules among total electronic energies of some triple molecular sets to the employed computational level. To achieve the goal, seven randomly generated hybrid functionals have been constructed and employed for calculation on a test set of 29 molecules containing second and third row elements. The computational results based on these nonoptimized DFT methods in conjunction with those of standard B3LYP method clearly demonstrates that in contrast to atomization or isomerization energies, additive rules among total electronic energies are insensitive to reliability or precision of computational method. This insensitivity to details of exchange‐correlation functional indicates that additive rules can be generally well considered using simple computational methods. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009

A database of chemical compositions of Persian medicinal herbs

Motivation: Herbal compounds exhibit a rich source of diverse molecular scaffolds with a high lev... more Motivation: Herbal compounds exhibit a rich source of diverse molecular scaffolds with a high level of structural complexity that is crucial for in silico and in vitro screening in the drug discovery process. Results: The Persian Herbal Constituents Database (PHCD) has been designed as a free webserver for providing useful information on many famous Persian medicinal herbs and their phytochemical ingredients. The PHCD facilitate in-depth plant and chemical searches by name, physicochemical properties, substructure, and molecular similarity using multiple advanced search functions.

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ET‐score: Improving Protein‐ligand Binding Affinity Prediction Based on Distance‐weighted Interatomic Contact Features Using Extremely Randomized Trees Algorithm

Molecular Informatics, May 21, 2021

The molecular docking simulation is a key computational tool in modern drug discovery research th... more The molecular docking simulation is a key computational tool in modern drug discovery research that its predictive performance strongly depends on the employed scoring functions. Many recent studies have shown that the application of machine learning algorithms in the development of scoring functions has led to a significant improvement in docking performance. In this work, we introduce a new machine learning (ML) based scoring function called ET‐Score, which employs the distance‐weighted interatomic contacts between atom type pairs of the ligand and the protein for featurizing protein−ligand complexes and Extremely Randomized Trees algorithm for the training process. The performance of ET‐Score is compared with some successful ML‐based scoring functions and several popular classical scoring functions on the PDBbind 2016v core set. It is shown that our ET‐Score model (with Pearson's correlation of 0.827 and RMSE of 1.332) achieves very good performance in comparison with most of the ML‐based scoring functions and all classical scoring functions despite its extremely low computational cost. ET‐Score's codes are freely available on the web at https://github.com/miladrayka/ET_Score.

CCDC 1838415: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Identification of Catechins’ Binding Sites in Monomeric Aβ42 through Ensemble Docking and MD Simulations

International Journal of Molecular Sciences

The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Al... more The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline—in the framework of the ensemble docking strategy—to identify catechins’ binding sites in monomeric Aβ42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ42. Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Aβ. Our findings are evaluated and confirmed with multi-micros...

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Interactions of Curcumin’s Degradation Products with the Aβ42 Dimer: A Computational Study

The Journal of Physical Chemistry B

Amyloid-β (Aβ) dimers are the smallest toxic species along the amyloid aggregation pathway and am... more Amyloid-β (Aβ) dimers are the smallest toxic species along the amyloid aggregation pathway and among the most-populated oligomeric accumulations present in the brain affected by Alzheimer's disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aβ into higher order structures is to develop molecules that inhibit the early stages of aggregation, i.e. dimerization. Under physiological conditions the Aβ dimer is highly dynamic and does not attain a single well defined structure but is rather characterized by an ensemble of conformations. In a recent work, a highly heterogeneous library of conformers of the Aβ dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aβ dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomistic detail of the interactions between the curcumin degradation products and the Aβ dimer. The simulations show that the aromatic residues of Aβ, and in particular 19 FF 20 interact with ferulic aldehyde and vanillin through π−π stacking. The binding of these small molecules induces significant changes on the 16 KLVFF 20 region.

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Interactions of curcumin’s degradation products with the Aβ42 dimer: A computational study

ABSTRACTAmyloid-β (Aβ) dimers are the smallest toxic species along the amyloid aggregation pathwa... more ABSTRACTAmyloid-β (Aβ) dimers are the smallest toxic species along the amyloid aggregation pathway and among the most-populated oligomeric accumulations present in the brain affected by Alzheimer’s disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aβ into higher order structures is to develop molecules that inhibit the early stages of aggregation, i.e. dimerization. Under physiological conditions the Aβ dimer is highly dynamic and does not attain a single well defined structure but is rather characterized by an ensemble of conformations. In a recent work, a highly heterogeneous library of conformers of the Aβ dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aβ dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomist...

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Electrostatically induced pKa shifts in oligopeptides: the upshot of neighboring side chains

Amino Acids

p K a values of homorepeat hexapeptides with a 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) chromophore... more p K a values of homorepeat hexapeptides with a 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO) chromophore attached at the peptide C termini, through an asparagine derivative (Dbo), namely His 6 –Dbo ( H 6 ), Lys 6 –Dbo ( K 6 ), and Arg 6 –Dbo ( R 6 ), were determined by a novel fluorescence-based method. The fluorescence lifetime of Dbo in the peptides ( τ ) was measured as a function of pH. The side chains collide with Dbo intramolecularly and quench it efficiently only when they are deprotonated (i.e., pH ≥ side chain p K a ). The p K a values of the H 6 , K 6 , and R 6 peptides, attributable to side chain ionization, were found to be depressed compared to the p K a values of the His, Lys, and Arg residues in their free amino acid forms. We further looked into the structural changes of the peptides by molecular dynamics (MD) simulations; the peptides were structurally more expanded when their side chains are protonated. The structural expansion of the peptides reflects an electrostatic repulsion between the protonated side chain residues, which also accounts for the observed decrease in p K a values, which corresponds to a facilitated deprotonation, assisted by electrostatic repulsion.

Constructing conformational library for amyloid-β42 dimers as the smallest toxic oligomers using two CHARMM force fields

Journal of Molecular Graphics and Modelling

Identification of potential anti-COVID-19 drug leads from Medicinal Plants through Virtual High-Throughput Screening

Natural compounds are widely used as attractive and valuable starting points for drug lead discov... more Natural compounds are widely used as attractive and valuable starting points for drug lead discovery. The present study aims to identify phytochemical compounds found in medicinal plants as potential COVID-19 inhibitors, using ensemble docking simulations. To this end, a phytochemical library from the PHCD database – a database of natural chemical compositions of Persian medicinal herbs (https://persianherb.com) – have been virtually screened against four key protein targets in the SARS-CoV-2 life cycle – the Mpro and PLpro proteases and the Spike and human ACE2 proteins. Several potential antiviral lead candidates have been identified based on the “Computational Multitarget Screening” approach, in which favourite candidates interact simultaneously with all four targets. Four of the bioactive phytochemicals identified – Chelidimerine, Gallagyldilacton, Hinokiflavone, and Physalin Z – show the highest binding afﬁnities to all the targets and are suggested to be the best choices for d...

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A database of chemical compositions of Persian medicinal herbs

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Identification of Catechins Binding Pockets in Monomeric Aβ42 Through Ensemble Docking and MD Simulations

The assembly of the Amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Al... more The assembly of the Amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline – in the framework of the ensemble docking strategy – to identify catechins’ binding pockets in monomeric Aβ42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ42. Also, it has been found that all the studied ligands, especially the EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of the Aβ. Our findings are evaluated and confirmed with multi-...

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Ensemble learning from ensemble docking: revisiting the optimum ensemble size problem

Scientific Reports, 2022

Despite considerable advances obtained by applying machine learning approaches in protein–ligand ... more Despite considerable advances obtained by applying machine learning approaches in protein–ligand affinity predictions, the incorporation of receptor flexibility has remained an important bottleneck. While ensemble docking has been used widely as a solution to this problem, the optimum choice of receptor conformations is still an open question considering the issues related to the computational cost and false positive pose predictions. Here, a combination of ensemble learning and ensemble docking is suggested to rank different conformations of the target protein in light of their importance for the final accuracy of the model. Available X-ray structures of cyclin-dependent kinase 2 (CDK2) in complex with different ligands are used as an initial receptor ensemble, and its redundancy is removed through a graph-based redundancy removal, which is shown to be more efficient and less subjective than clustering-based representative selection methods. A set of ligands with available experime...

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Seeking Extremes in Molecular Design: To What Extent May Two “Non-Bonded” Hydrogen Atoms be Squeezed in a Hydrocarbon?

ChemPhysChem, 2015

A series of novel and possibly synthetically accessible rigid hydrocarbon structures is computati... more A series of novel and possibly synthetically accessible rigid hydrocarbon structures is computationally introduced, maintaining ultrashort non-bonded hydrogen-hydrogen (H⋅⋅⋅H) contacts smaller than 1.2 Å. These are the shortest non-bonded H⋅⋅⋅H contacts reported to date, bypassing previous world records of both experimentally observed, 1.56 Å, and computationally derived, 1.4 Å, H⋅⋅⋅H contacts in any stable molecular structure.

Introduction of a novel additivity scheme coincidence with homodesmicity concept for (CH)xNy (x+y=6) molecules

Journal of Molecular Structure: THEOCHEM, 2008

ABSTRACT In this study, group additivity corresponding to ab initio derived total electronic ener... more ABSTRACT In this study, group additivity corresponding to ab initio derived total electronic energies among all members of triple sets of nitrogen-containing heterocyclic six-membered ring molecules has been investigated by suggesting two additivity schemes. It has been demonstrated that, almost all triple sets conforming to the newly presented additivity scheme have been predicted to be additive. On the contrary, by using the groups (defined as a polyvalent atom in a molecule together with all of its ligands), group additivity of above-mentioned sets cannot be predicted at all. We have introduced “homodesmicity” criterion as a general and more reliable tool than known prerequisite condition of groups conservation to predict existence of group additivity in these molecules. In addition, it has been shown that group additivity is insensitive to the combination of methods and basis sets used to drive the total electronic energies.

Ab initio studies of BN-acenes and cyclo BN-acenes electronic properties and their dependence on the molecular size and the number of electrons

Journal of Molecular Structure: THEOCHEM, 2009

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Rohoullah Firouzi

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