Publications by authors named "Vladimir Potemkin"

34 Publications

Complementarity principle in terms of electron density for the study of EGFR complexes.

Future Med Chem 2021 Apr 13. Epub 2021 Apr 13.

Laboratory of Computational Modeling of Drugs, Higher Medical & Biological School, South Ural State University, Chelyabinsk, 454008, Russia.

The complementarity principle is a well-established concept in the field of chemistry and biology. This concept is widely studied as the lock-and-key relationship between two structures, such as enzyme and ligand interactions. These interactions are based on the overlap of electron clouds between two structures. In this study, a mathematical relation determining complementarity of intermolecular contacts in terms of overlaps of electron clouds was examined using a quantum orbital-free AlteQ method developed in-house for 64 EGFR-ligand complexes with experimentally measured binding affinity data. A very high correlation was found between the overlap of ligand and enzyme electron clouds and the calculated terms, providing a good basis for prognosis of bioactivity and for molecular docking studies.
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http://dx.doi.org/10.4155/fmc-2020-0265DOI Listing
April 2021

Use of the Complementarity Principle in Docking Procedures: A New Approach for Evaluating the Correctness of Binding Poses.

J Chem Inf Model 2021 Apr 2. Epub 2021 Apr 2.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chaikovskogo 20A, Chelyabinsk 454008, Russia.

Even though the first docking procedures were developed almost 40 years ago, they are still under intense development, alongside with their validation. In this article, we are proposing the use of the quantum free-orbital AlteQ method in evaluating the correctness of ligand binding poses and their ranking. The AlteQ method calculates the electron density in the interspace between the ligand and the receptor, and since their interactions follow the maximum complementarity principle, an equation can be obtained, which describes these interactions. In this way, the AlteQ method evaluates the quality of contacts between the ligand and the receptor, bypasses the drawbacks of using ligand RMSD as a measure of docking quality, and can be considered as an improvement of the "fraction of recovered ligand-receptor contacts" method. Free Windows and Linux versions of the AlteQ program for assessing complementarity between the ligand and the receptor are available for download at www.chemosophia.com.
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http://dx.doi.org/10.1021/acs.jcim.0c01382DOI Listing
April 2021

Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin-1,2,4-triazole scaffolds.

Arch Pharm (Weinheim) 2021 Mar 3:e2000473. Epub 2021 Mar 3.

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Prayagraj, Uttar Pradesh, India.

Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine-1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods ( H and C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure-activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.
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http://dx.doi.org/10.1002/ardp.202000473DOI Listing
March 2021

Can natural products stop the SARS-CoV-2 virus? A docking and molecular dynamics study of a natural product database.

Future Med Chem 2021 02 8;13(4):363-378. Epub 2021 Jan 8.

Higher Medical & Biological School, Laboratory of Computational Modeling of Drugs, South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk 454080, Russia.

The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.
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http://dx.doi.org/10.4155/fmc-2020-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798421PMC
February 2021

Electronic properties investigation of human dihydrofolate reductase complexes with ligands.

J Biomol Struct Dyn 2020 Dec 21:1-16. Epub 2020 Dec 21.

Department of Chemistry, College of Science, Deanship of Scientific Research, Taif University, Taif, Saudi Arabia.

Despite the fact that there are already drugs for cancer, they still show strong toxicity to the human organism. That is why it is necessary to establish the factors affecting activity in order to develop new, more effective drugs aimed at tumor cells, minimizing harm to healthy cells. The present research is based on electronic properties calculation of the complexes using AlteQ approach. In the focus of this study are complexes of human dihydrofolate reductase (hDHFR) with a series of known inhibitors bound in the active site. Further, a statistical analysis was performed to establish the relationships between a myriad electronic characteristics and IC. The change in total volume and the change of own electrons number of hydrogen atoms in their atomic basins are identified as the descriptors correlating the most with the hDHFR inhibition potency. Additionally, two lipophilic parts of protein (Thr56, Ser59, Ile60 and Ile7, Val8, Ala9) were found, which act as a key factor in decreasing bioactivity. The depth analysis of intermolecular interactions showed that the interactions between water molecules and ligand play a crucial role in hDHFR inhibition. Furthermore, the molecular dynamics simulations were used for deeper understanding of the structural inhibition, each for 50 ns time scale in explicit water conditions. Thus, the AlteQ approach made it possible to determine the factors influencing the activity and evaluate them not only qualitatively, but also quantitatively. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1861985DOI Listing
December 2020

Hybrid Quinazoline 1,3,5-Triazines as Epidermal Growth Factor Receptor (EGFR) Inhibitors with Anticancer Activity: Design, Synthesis, and Computational Study.

ChemMedChem 2021 Mar 1;16(5):822-838. Epub 2020 Dec 1.

Laboratory of Computational Modelling of Drugs, South Ural State University, Chaikovskogo 20A, Chelyabinsk, 454008, Russia.

We report a series of hybrid quinazoline-1,3,5-triazine derivatives as EGFR inhibitors, which were synthesised and tested by using a variety of in vitro, in silico, and in vivo techniques. The derivatives were found to be active against different cancer cell lines and nontoxic against normal ones, with compounds 7 c, 7 d, 7 e, and 7 j being the most potent ones. The derivatives were also evaluated for angiogenesis inhibition potency in chicken eggs, and molecular docking and dynamics simulation studies were carried out to elucidate the fundamental substituent groups essential for their bioactivity. Additionally, a SAR study of the derivatives was performed for future compound optimisation. These studies suggested that the derivatives have a high affinity towards EGFR with favourable pharmacological properties. The most active compound (7 e) was further evaluated for in vivo anticancer activity against DMBA-induced tumours in female Sprague-Dawley rats as well as its effects on plasma antioxidant status, biotransformation enzymes, and lipid profile. The study suggested that 7 e has lead properties against breast cancer and can serve as a starting compound for further development of anti-EGFR compounds.
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http://dx.doi.org/10.1002/cmdc.202000646DOI Listing
March 2021

Computational insights into the binding mode of curcumin analogues against EP300 HAT domain as potent acetyltransferase inhibitors.

J Mol Graph Model 2020 12 16;101:107756. Epub 2020 Sep 16.

Department of PG Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Jnana Sahyadri, Shankaraghatta, Shivamogga, 577451, Karnataka, India; Department of Biochemistry, Jnana Bharathi Campus, Bangalore University, Bangalore, Karnataka, 560056, India. Electronic address:

Acetylation plays a key role in maintaining and balancing cellular regulation and homeostasis. Acetyltransferases are an important class of enzymes which mediate this acetylation process. EP300 is a type 3 major lysine (K) acetyl transferase, and its aberrant activity is implicated in many human diseases. Hence, targeting EP300 mediated acetylation is a necessary step to control the associated diseases. Currently, a few EP300 inhibitors are known, among which curcumin is the most widely investigated molecule. However, due to its instability, chemical aggregation and reactivity, its inhibitory activity against the EP300 acetyltransferase domain is disputable. To address this curcumin problem, different curcumin analogues have been synthesized. These molecules were selected for screening against the EP300 acetyltransferase domain using in silico docking and MD analysis. We have successfully elucidated that the curcumin analogue CNB001 is a potential EP300 inhibitor with good drug-like characteristics.
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http://dx.doi.org/10.1016/j.jmgm.2020.107756DOI Listing
December 2020

The study of EGFR-ligand complex electron property relationship with biological activity.

J Biomol Struct Dyn 2020 Sep 8:1-14. Epub 2020 Sep 8.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.

The present investigation grounded on estimation of electron properties of the structures of EGFR proteins-ligand complexes using our laboratory-developed methodology AlteQ approach, which describes the molecular electron density of the complex in space for a certain point in three-dimensional coordinates. Briefly, the system embodies molecular electron density as a sum of Slater's type atomic increments of the molecular system. Further, using this methodology, we calculated different electron characteristics of selected EGFR protein-ligand complexes and established the relationship between different electron properties with their experimental pharmacological activity value (pIC). The study suggested that EGFR inhibitory activity has higher correlation with intermolecular contacts of H with pi-system of aromatic ring between protein and ligands. Therefore, this created model has impact to identify and design potential ligands against EGFR in anticancer drug discovery. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1813629DOI Listing
September 2020

Experimental and Computational Studies of Microwave-Assisted, Facile Ring Opening of Epoxide with Less Reactive Aromatic Amines in Nitromethane.

ACS Omega 2020 Aug 21;5(30):18746-18757. Epub 2020 Jul 21.

Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India.

Nucleophilic ring opening reactions of epoxides with aromatic amines are in the forefront of the synthetic organic chemistry research to build new bioactive scaffolds. Here, convenient, green, and highly efficient regioselective ring opening reactions of sterically hindered (2,3)-3-(-Boc-amino)-1-oxirane-4-phenylbutane with various poorly reactive aromatic amines are accomplished under microwave irradiation in nitromethane. All the reactions effectively implemented for various aromatic amines involve the reuse of nitromethane that supports its dual role as a solvent and catalyst. The corresponding new β-alcohol analogs of hydroxyethylamine (HEA) are isolated in 41-98% yields. The reactions proceed under mild conditions for a broad range of less reactive and sterically hindered aromatic amines. Proton NMR experiments suggest that the nucleophilicity of amines is influenced by nitromethane, which is substantiated by the extensive computational studies. Overall, this methodology elucidates the first-time use of nitromethane as a solvent for the ring opening reactions under microwave conditions involving an equimolar ratio of epoxide and aromatic amine without any catalyst, facile ring opening of complex epoxide by less reactive aromatic amines, low reaction time, less energy consumption, recycling of the solvent, and simple workup procedures.
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http://dx.doi.org/10.1021/acsomega.0c01760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408245PMC
August 2020

Electron density analysis of CDK complexes using the AlteQ method.

Future Med Chem 2020 08 21;12(15):1387-1397. Epub 2020 Jul 21.

Laboratory of Computational Modeling of Drugs, Higher Medical & Biological School, South Ural State University, Chelyabinsk, 454008, Russia.

A principle of complementarity is a well-established concept in chemistry and biology. This concept is based on the overlap of electron clouds of the molecules in question. In this article, one such approach (an in-house developed quantum free-orbital AlteQ method) was used to evaluate the complementarity of 51 CDK-ligand complexes. A significant universally applicable correlation (adjusted R = 0.9749; p < 2.2 × 10) relating the product of ligand and enzyme electron densities to the product of distances between the contacting atomic centers and the type of atoms involved in the interaction was found. The terms calculated in this article can provide a good basis for prognosis of bioactivity and scientifically based molecular docking.
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http://dx.doi.org/10.4155/fmc-2020-0076DOI Listing
August 2020

Classification and functional analyses of putative virulence factors of Mycobacterium tuberculosis: A combined sequence and structure based study.

Comput Biol Chem 2020 May 5;87:107270. Epub 2020 May 5.

Department of Chemistry, Faculty of Science, King Abdulaziz University, P.O. Box 80203 Jeddah 21589, Saudi Arabia; Department of Chemistry, Faculty of Science, Port Said University, Port Said, 42521, Egypt.

The emergence of the drug-resistant mechanisms in Mycobacterium tuberculosis poses the biggest challenges to the current therapeutic measures, which necessitates the identification of new drug targets. The Hypothetical Proteins (HPs), a class of functionally uncharacterized proteins, may provide a new class of undiscovered therapeutic targets. The genome of M. tuberculosis contains 1000 HPs with their sequences were analyzed using a variety of bioinformatics tools and the functional annotations were performed. The functions of 662 HPs were successfully predicted and further classified 483 HPs as enzymes, 141 HPs were predicted to be involved in the diverse cellular mechanisms and 38 HPs may function as transporters and carriers proteins. Furthermore, 28 HPs were predicted to be virulent in nature. Amongst them, the HP P95201, HP P9WM79, HP I6WZ30, HP I6 × 9T8, HP P9WKP3, and HP P9WK89 showed the highest virulence scores. Therefore, these proteins were subjected to extensive structure analyses and dynamics of their conformations were investigated using the principles of molecular dynamics simulations, each for a 150 ns time scale. This study provides a deeper understanding of the undiscovered drug targets and the generated outputs will facilitate the process of drug design and discovery against the infection of M. tuberculosis.
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http://dx.doi.org/10.1016/j.compbiolchem.2020.107270DOI Listing
May 2020

Study of Short Peptide Adsorption on Solution Dispersed Inorganic Nanoparticles Using Depletion Method.

J Vis Exp 2020 04 11(158). Epub 2020 Apr 11.

Nanotechnology Education and Research Center, South Ural State University;

Fundamentals of inorganic-organic interactions are critically important in the discovery and development of novel biointerfaces amenable for utilization in biotechnology and medicine. Recent studies indicate that proteins interact with surfaces through limited adsorption sites. Protein fragments such as amino acids and peptides can be used for interaction modeling between complex biological macromolecules and inorganic surfaces. During the last three decades, many valid and sensitive methods have been developed to measure the physical chemistry fundamentals of those interactions: isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), quartz crystal microbalance (QCM), total internal reflection fluorescence (TIRF), and attenuated total reflectance spectroscopy (ATR). The simplest and most affordable technique for the measurement of adsorption is the depletion method, where the change in sorbate concentration (depletion) after contact with solution-dispersed sorbent is calculated and assumed to be adsorbed. Adsorption isotherms based on depletion data provide all basic physicochemical data. However, adsorption from solutions requires longer equilibration times due to kinetic restrictions and sorbents with a high specific surface area, making it almost inapplicable to macroscopic fixed plane surfaces. Moreover, factors such as the instability of sols, nanoparticle aggregates, sorbent crystallinity, nanoparticle size distribution, pH of the solution, and competition for adsorption, should be considered while studying adsorbing peptides. Depletion data isotherm construction provides comprehensive physical chemistry data for literally every soluble sorbate yet remains the most accessible methodology, as it does not require expensive setups. This article describes a basic protocol for the experimental study of peptide adsorption on inorganic oxide and covers all critical points that affect the process.
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http://dx.doi.org/10.3791/60526DOI Listing
April 2020

Novel radial distribution function approach in the study of point mutations: the HIV-1 protease case study.

Future Med Chem 2020 06 22;12(11):1025-1036. Epub 2020 Apr 22.

Higher Medical & Biological School, Laboratory of Computational Modeling of Drugs, South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk, 454080, Russia.

Mutations are one of the engines of evolution. Under constant stress pressure, mutations can lead to the emergence of unwanted, drug-resistant entities. The radial distribution function weighted by the number of valence shell electrons is used to design quantitative structure-activity relationship (QSAR) model relating descriptors with the inhibition constant for a series of wild-type HIV-1 protease inhibitor complexes. The residuals of complexes with mutant HIV-1 protease were correlated with the energy of the highest occupied molecular orbitals of the residues introduced to enzyme via point mutations. Successful identification of residues Ile3, Asp25, Val32 and Ile50 as the one whose substitution influences the inhibition constant the most, demonstrates the potential of the proposed methodology for the study of the effects of point mutations.
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http://dx.doi.org/10.4155/fmc-2020-0042DOI Listing
June 2020

Performance of radial distribution function-based descriptors in the chemoinformatic studies of HIV-1 protease.

Future Med Chem 2020 02 27;12(4):299-309. Epub 2020 Jan 27.

Computer-Chemie-Centrum, Friedrich-Alexander-University Erlangen-Nürnberg, Naegelsbachstr. 25, 91052, Erlangen, Germany.

This letter investigates the role of radial distribution function-based descriptors for design of new drugs. The multiple linear regression models for HIV-1 protease and its complexes with a series of inhibitors were constructed. A detailed analysis of major atomic contributions to the radial distribution function descriptor weighted by the number of valence shell electrons identified residues Arg8, Asp29 and residues of the catalytic triad as crucial for the correlation with the inhibition constant, together with residues Asp30 and Ile50, whose mutations are known to cause an emergence of drug resistant variants. This study demonstrates an easy and fast assessment of the activity of potential drugs and the derivation of structural information of their complexes with the receptor or enzyme.
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http://dx.doi.org/10.4155/fmc-2019-0241DOI Listing
February 2020

The Influence of Hydrogen atoms on the Performance of Radial Distribution Function Based Descriptors in the Chemoinformatic Studies of HIV-1 Prote-ase Complexes with Inhibitors.

Curr Drug Discov Technol 2020 Jan 2. Epub 2020 Jan 2.

South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk 454080, Russian Federation.

In this letter the newly introduced approach based on the radial distribution function (RDF) weighted by the number of va-lence shell electrons is applied for a series of HIV-1 protease enzyme and its complexes with inhibitors to evaluate the influ-ence of hydrogen atoms on the performance of the model. The multiple linear regression method was used for the selection of the relevant descriptors. Two groups of residues having dominant contribution to the RDF descriptor are identified as relevant for the inhibition. In the first group are residues like Arg8, Asp25, Thr26, Gly27 and Asp29, which establish direct interaction with the inhibitor, while the second group consists of the amino acids at the interface of the two homodimer sub-units or with the solvent. The crucial motif pointed out by our approach as the most important for inhibition of the enzyme's activity and present in all inhibitors is hydroxyl group that establish hydrogen bond with Asp25 side chain. Additionally, the comparison to the model without hydrogen showed that both models are of similar quality, but the downside of the current model is the need for the determination of residues' protonation states.
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http://dx.doi.org/10.2174/1570163817666200102130415DOI Listing
January 2020

Nonparametric chemical descriptors for the calculation of ligand-biopolymer affinities with machine-learning scoring functions.

J Comput Aided Mol Des 2019 11 14;33(11):943-953. Epub 2019 Nov 14.

South Ural State University, 20A Tchaikovsky Street, Chelyabinsk, Russian Federation, 454080.

The computational prediction of ligand-biopolymer affinities is a crucial endeavor in modern drug discovery and one that still poses major challenges. The choice of the appropriate computational method often reveals itself as a trade-off between accuracy and speed, with mathematical devices referred to as scoring functions being the fastest. Among the many shortcomings of scoring functions there is the lack of universal applicability to every molecular system. This is so largely due to their reliance on atom type perception and/or parametrization. This article proposes the use of nonparametric Model of Effective Radii of Atoms descriptors that can be readily computed for the entire Periodic Table and demonstrate that, in combination with machine learning algorithms, they can yield competitive performances and chemically meaningful insights.
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http://dx.doi.org/10.1007/s10822-019-00248-2DOI Listing
November 2019

1,2,4-Triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds: A potent ameliorant of carrageenan-induced inflammation by lessening proinflammatory mediators.

Arch Pharm (Weinheim) 2020 Jan 7;353(1):e1900233. Epub 2019 Nov 7.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.

Inflammation acts as an alarming signal for the progression of various biological complications. Various reports in the literature have revealed that heterocycle-containing synthetic compounds have a restorative capability against acute and chronic inflammatory stages. In the current study, we synthesized a series of 1,2,4-triazole-conjugated 1,3,4-thiadiazole hybrid scaffolds and evaluated their impacts against carrageenan-induced paw edema and proinflammatory markers in Wistar rats. Further, 3D QSAR study (three-dimensional quantitative structure-activity relationships), ADMET (absorption, distribution, metabolism, and excretion) profiling, and docking studies were performed to determine the possible mechanism of the action of the derivatives. The study shows that the most active derivatives, 13f and 13g, have optimal logP, a higher anti-inflammatory activity score, and poor metabolism at various sites of cytochrome P450. The docking studies recommended that the synthesized compounds have a similar affinity as the ligands A307, 63X, and S58 to interact with tumor necrosis factor-α, COX-1, and COX-2. So, these molecules will definitely hold a promise for the future drug development initiative.
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http://dx.doi.org/10.1002/ardp.201900233DOI Listing
January 2020

The structural basis of acid resistance in : insights from multiple pH regime molecular dynamics simulations.

J Biomol Struct Dyn 2020 Sep 8;38(15):4483-4492. Epub 2019 Nov 8.

Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India.

The dormant is evolved to develop the tolerance against the acidification of phagolysosome by the action of gamma interferon. The molecular mechanism responsible for the development of the resistance towards the acidic conditions in is not fully understood. Therefore, the current analysis was performed which studies the mechanism of acid tolerance by correlating the alteration in the protonation state of conserved residues in virulent proteins with changes in their folding states. The pH dependencies of proteins were studied using an efficient computational scheme which enables the understanding of their conformational behavior by molecular dynamics (MD) simulations. The adopted methodology involves cyclically updating of the ionization states of titrable residues in the studied proteins with conventional MD steps, which were applied to the newly generated ionization configuration. Significant pH-dependent protein structural stability parameters consistent with the changes of the protonation states of conserved residues were observed. Among the studied proteins, the peptidoglycan binding protein ompATB, carboxylesterase LipF and two-component systems' transcriptional regulator PhoP showed highest structural conservation in the observed acidic pH range throughout the course of MD simulations. The current study provides a better understanding of acid tolerance mechanisms present in and can facilitate the drug development strategies against the dormant protein targets.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1682676DOI Listing
September 2020

Quinazoline based 1,3,5-triazine derivatives as cancer inhibitors by impeding the phosphorylated RET tyrosine kinase pathway: Design, synthesis, docking, and QSAR study.

Arch Pharm (Weinheim) 2019 Sep 5;352(9):e1900053. Epub 2019 Aug 5.

Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, Russia.

The present research focused on designing a quinazoline skeleton, framed via 1,3,5-triazine derivatives (QBT) through field mapping and alignment studies. The QBT derivatives were synthesized via time- and cost-effective protocol. The 3D-QSAR study, computational physicochemical properties, and ADME calculation of the derivatives were performed to establish the affinity towards the biological system. Molecular docking in the adenosine triphosphate binding site of the RET tyrosine kinase domain (PDB ID: 7IVU) was studied to elucidate vital structural residues necessary for bioactivity. The derivatives were evaluated for anticancer potency against TPC-1 cells (thyroid cancer), MCF-7 cells (breast cancer), and one normal cell line (human foreskin fibroblasts) via 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide assay followed by an in ovo CAM assay. The entire series of derivatives (8a-o) showed mild to significant anticancer potency against the selected cancer cell lines.
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http://dx.doi.org/10.1002/ardp.201900053DOI Listing
September 2019

Adsorption of Native Amino Acids on Nanocrystalline TiO: Physical Chemistry, QSPR, and Theoretical Modeling.

Langmuir 2019 01 28;35(2):538-550. Epub 2018 Dec 28.

Department of Chemical and Environmental Engineering , University of Oviedo , 33006 Oviedo , Spain.

The affinity of biomolecules, such as peptides and proteins, with inorganic surfaces, is a fundamental topic in biotechnology and bionanotechnology. Amino acids are often used as "model" bits of peptides or proteins for studying their properties in different environments and/or developing functional surfaces. Despite great demand for knowledge about amino acid interactions with metal oxide surfaces, studies on the issue represent a fragmentary picture. In this paper, we describe amino acid adsorption on nanocrystalline anatase systematically at uniform conditions. Analysis of the Gibbs free adsorption energy indicated how the aliphatic, aromatic, polar, and charged side chain groups affect the binding affinity of the amino acids. Thermodynamic features of the l-amino acid adsorption receive thorough interpretation with calculated molecular descriptors. Theoretical modeling shows that amino acids complex with TiO nanoparticles as zwitterions via ammonium group.
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http://dx.doi.org/10.1021/acs.langmuir.8b02007DOI Listing
January 2019

Internet Resources for Drug Discovery and Design.

Curr Top Med Chem 2018 ;18(22):1955-1975

Laboratory of Computational Modeling of Drugs, South Ural State University, Pr. Lenina, 76, Chelyabinsk 454080, Russian Federation.

The review describes online resources used for drug discovery and design. Internet resources can be classified into two classes. The first class of resources accumulates information about drugs, drug candidates, compounds, and bioassays. This information is a starting point in drug discovery and design. It is necessary for a training dataset composition. The data found at this step are needed in the search for the rules predicting a biological activity or recognizing active compounds among other molecules. The following databases can be used: ChEMBL, different databases of US National Institutes of Health, DrugBank, PDBind-CN Database, RCSB Protein Data Bank (PDB), BRENDA, etc. The second class of Internet resources includes web-portals performing online computations for drug discovery and design. The web-portals perform: 1) modelling of molecular structure such as geometry optimization and molecular docking; 2) online computations of various descriptors, physical-chemical and ADMET properties influencing the bioprocesses occurring in a living organism along the road of the drug therapeutic action; 3) quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) studies; 4) prognosis of bioactivities of compounds; 5) design of new drug candidates. These are, for example, ChemAxon, ACD/ I-lab, Mcule, OCHEM, eADMET, ChemoSophia, DockingServer, 1-click Docking, MDWeb, DockingServer, ZDOCK, etc. The role of docking online resources for modeling of "ligand-receptor" complexes, prognosis of bioactivities, and drug design is discussed. The review highlights the possibilities of Internet resources for a study of a drug action at the most important stages. A detailed assessment of the advantages of the reviewed Internet resources is done.
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http://dx.doi.org/10.2174/1568026619666181129142127DOI Listing
January 2019

Topological Analysis of Electron Density in Large Biomolecular Systems.

Curr Drug Discov Technol 2019 ;16(4):437-448

South Ural State University, Laboratory of Computational Modelling of Drugs, Tchaikovsky str. 20-A, Chelyabinsk, Russian Federation.

Background: A great step toward describing the structure of the molecular electron was made in the era of quantum chemical methods. Methods play a very important role in the prediction of molecular properties and in the description of the reactivity of compounds, which cannot be overestimated. There are many works, books, and articles on quantum methods, their applications, and comparisons. At the same time, quantum methods of a high level of theory, which give the most accurate results, are time-consuming, which makes them almost impossible to describe large complex molecular systems, such as macromolecules, enzymes, supramolecular compounds, crystal fragments, and so on.

Objectives: To propose an approach that allows real-time estimation of electron density in large systems, such as macromolecules, nanosystems, proteins.

Methods: AlteQ approach was applied to the tolopogical analysis of electron density for "substrate - cytochrome" complexes. The approach is based on the use of Slater's type atomic contributions. Parameters of the atomic contributions were found using high resolution X-ray diffraction data for organic and inorganic molecules. Relationships of the parameters with atomic number, ionization potentials and electronegativities were determined. The sufficient quality of the molecular electron structure representation was shown under comparison of AlteQ predicted and observed electron densities. AlteQ algorithm was applied for evaluation of electron structure of "CYP3A4 - substrate" complexes modeled using BiS/MC restricted docking procedure. Topological analysis (similar to Atoms In Molecules (AIM) theory suggested by Richard F.W. Bader) of the AlteQ molecular electron density was carried out for each complex. The determination of (3,-1) bond, (3,+1) ring, (3,+3) cage critical points of electron density in the intermolecular "CYP3A4 - substrate" space was performed.

Results: Different characteristics such as electron density, Laplacian eigen values, etc. at the critical points were computed. Relationship of pKM (KM is Michaelis constant) with the maximal value of the second Laplacian eigen value of electron density at the critical points and energy of complex formation computed using MM3 force field was determined.

Conclusion: It was shown that significant number of (3,-1) bond critical points are located in the intermolecular space between the enzyme site and groups of substrate atoms eliminating during metabolism processes.
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http://dx.doi.org/10.2174/1570163815666180821165330DOI Listing
August 2020

Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors.

Bioorg Med Chem 2018 07 28;26(13):3837-3844. Epub 2018 Jun 28.

Laboratory for Translational Chemistry and Drug Discovery, Department of Chemistry, Hansraj College, University of Delhi, Delhi 110007, India; South Ural State University, Laboratory of Computational Modeling of Drugs, 454080, Russia. Electronic address:

Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (K, 1.93 ± 0.29 µM for Plm II; K, 1.99 ± 0.05 µM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (K, 0.84 ± 0.08 µM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC, 2.27 ± 0.95 µM for 10f; IC, 3.11 ± 0.65 µM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC value of 1.35 ± 0.85 µM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules.
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http://dx.doi.org/10.1016/j.bmc.2018.06.037DOI Listing
July 2018

Grid-Based Technologies for In Silico Screening and Drug Design.

Curr Med Chem 2018 ;25(29):3526-3537

South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk 454080, Russian Federation.

Various techniques for rational drug design are presented in the paper. The methods are based on a substitution of antipharmacophore atoms of the molecules of training dataset by new atoms and/or group of atoms increasing the atomic bioactivity increments obtained from an SAR study. Furthermore, a design methodology based on the genetic algorithm DesPot for discrete optimization and generation of new drug candidate structures is described. Additionally, wide spectra of SAR approaches (3D/4D QSAR interior and exterior-based methods - BiS, CiS, ConGO, CoMIn, high-quality docking method - ReDock) using MERA force field and/or AlteQ quantum chemical method for correct prognosis of bioactivity and the bioactive probability have been described. The design methods are implemented at www.chemosophia.com web-site for online computational services.
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http://dx.doi.org/10.2174/0929867325666180309112454DOI Listing
October 2018

Grid-based Continual Analysis of Molecular Interior for Drug Discovery, QSAR and QSPR.

Curr Drug Discov Technol 2017 ;14(3):181-205

High School of Medicine and Biology, South Ural State University, 85, pr. Lenina, Chelyabinsk, 454080. Russian Federation.

Background: In 1979, R.D.Cramer and M.Milne made a first realization of 3D comparison of molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (Dynamic Lattice- Oriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities. Then, in 1988, the method which was called CoMFA (Comparative Molecular Field Analysis) was introduced and the appropriate software became commercially available. Since 1988, a lot of 3D QSAR methods, algorithms and their modifications are introduced for solving of virtual drug discovery problems (e.g., CoMSIA, CoMMA, HINT, HASL, GOLPE, GRID, PARM, Raptor, BiS, CiS, ConGO,). All the methods can be divided into two groups (classes):1. Methods studying the exterior of molecules; 2) Methods studying the interior of molecules.

Methods: A series of grid-based computational technologies for Continual Molecular Interior analysis (CoMIn) are invented in the current paper. The grid-based analysis is fulfilled by means of a lattice construction analogously to many other grid-based methods. The further continual elucidation of molecular structure is performed in various ways. (i) In terms of intermolecular interactions potentials. This can be represented as a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are well known continual functions and their values can be determined in all lattice points for a molecule. (ii) In the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum free-orbital approach AlteQ is proposed. All the functions can be calculated using a quantum approach at a sufficient level of theory and their values can be determined in all lattice points for a molecule. Then, the molecules of a dataset can be superimposed in the lattice for the maximal coincidence (or minimal deviations) of the potentials (i) or the quantum functions (ii).

Results: The methods and criteria of the superimposition are discussed. After that a functional relationship between biological activity or property and characteristics of potentials (i) or functions (ii) is created. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page.

Conclusion: Therefore, a set of 3D QSAR approaches for continual molecular interior study giving a lot of opportunities for virtual drug discovery, virtual screening and ligand-based drug design are invented. The continual elucidation of molecular structure is performed in the terms of intermolecular interactions potentials and in the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum free-orbital approach AlteQ is proposed. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page.
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http://dx.doi.org/10.2174/1570163814666170207144018DOI Listing
June 2018

An approximation of the Cioslowski–Mixon bond order indexes using the AlteQ approach.

J Comput Aided Mol Des 2013 Sep;27(9):793-805

Fast and reliable prediction of bond orders in organic systems based upon experimentally measured quantities can be performed using electron density features at bond critical points (J Am Chem Soc 105:5061–5068, 1983; J Phys Org Chem 16:133–141, 2003; Acta Cryst B 61:418–428, 2005; Acta Cryst B 63:142–150, 2007). These features are outcomes of low-temperature high-resolution X-ray diffraction experiments. However, a time-consuming procedure of gaining these quantities makes the prediction limited. In the present work we have employed an empirical approach AlteQ (J Comput Aided Mol Des 22:489–505, 2008) for evaluation of electron density properties. This approach uses a simple exponential function derived from comparison of electron density, gained from high-resolution X-ray crystallography, and distance to atomic nucleus what allows calculating density distribution in time-saving manner and gives results which are very close to experimental ones. As input data AlteQ accepts atomic coordinates of isolated molecules or molecular ensembles (for instance, protein–protein complexes or complexes of small molecules with proteins, etc.). Using AlteQ characteristics we have developed regression models predicting Cioslowski–Mixon bond order (CMBO) indexes (J Am Chem Soc 113(42):4142–4145, 1991). The models are characterized by high correlation coefficients lying in the range from 0.844 to 0.988 dependently on the type of covalent bond, thereby providing a bonding quantification that is in reasonable agreement with that obtained by orbital theory. Comparative analysis of CMBOs approximated using topological properties of AlteQ and experimental electron densities has shown that the models can be used for fast determination of bond orders directly from X-ray crystallography data and confirmed that AlteQ characteristics can replace experimental ones with satisfactory extent of accuracy.
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http://dx.doi.org/10.1007/s10822-013-9677-zDOI Listing
September 2013

ToxAlerts: a Web server of structural alerts for toxic chemicals and compounds with potential adverse reactions.

J Chem Inf Model 2012 Aug 10;52(8):2310-6. Epub 2012 Aug 10.

eADMET GmbH, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.

The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts, and it is constantly growing.
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http://dx.doi.org/10.1021/ci300245qDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640409PMC
August 2012

Compressibility of gas hydrates.

Chemphyschem 2011 Sep 29;12(13):2476-84. Epub 2011 Jun 29.

Nikolaev Institute of Inorganic Chemistry SB RAS, Akad. Lavrentiev ave., 3, Novosibirsk, 630090, Russian Federation.

Experimental data on the pressure dependence of unit cell parameters for the gas hydrates of ethane (cubic structure I, pressure range 0-2 GPa), xenon (cubic structure I, pressure range 0-1.5 GPa) and the double hydrate of tetrahydrofuran+xenon (cubic structure II, pressure range 0-3 GPa) are presented. Approximation of the data using the cubic Birch-Murnaghan equation, P=1.5B(0)[(V(0)/V)(7/3)-(V(0)/V)(5/3)], gave the following results: for ethane hydrate V(0)=1781 Å(3) , B(0)=11.2 GPa; for xenon hydrate V(0)=1726 Å(3) , B(0)=9.3 GPa; for the double hydrate of tetrahydrofuran+xenon V(0)=5323 Å(3) , B(0)=8.8 GPa. In the last case, the approximation was performed within the pressure range 0-1.5 GPa; it is impossible to describe the results within a broader pressure range using the cubic Birch-Murnaghan equation. At the maximum pressure of the existence of the double hydrate of tetrahydrofuran+xenon (3.1 GPa), the unit cell volume was 86% of the unit cell volume at zero pressure. Analysis of the experimental data obtained by us and data available from the literature showed that 1) the bulk modulus of gas hydrates with classical polyhedral structures, in most cases, are close to each other and 2) the bulk modulus is mainly determined by the elasticity of the hydrogen-bonded water framework. Variable filling of the cavities with guest molecules also has a substantial effect on the bulk modulus. On the basis of the obtained results, we concluded that the bulk modulus of gas hydrates with classical polyhedral structures and existing at pressures up to 1.5 GPa was equal to (9±2) GPa. In cases when data on the equations of state for the hydrates were unavailable, the indicated values may be recommended as the most probable ones.
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http://dx.doi.org/10.1002/cphc.201100126DOI Listing
September 2011

Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information.

J Comput Aided Mol Des 2011 Jun 10;25(6):533-54. Epub 2011 Jun 10.

eADMET GmbH, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.

The Online Chemical Modeling Environment is a web-based platform that aims to automate and simplify the typical steps required for QSAR modeling. The platform consists of two major subsystems: the database of experimental measurements and the modeling framework. A user-contributed database contains a set of tools for easy input, search and modification of thousands of records. The OCHEM database is based on the wiki principle and focuses primarily on the quality and verifiability of the data. The database is tightly integrated with the modeling framework, which supports all the steps required to create a predictive model: data search, calculation and selection of a vast variety of molecular descriptors, application of machine learning methods, validation, analysis of the model and assessment of the applicability domain. As compared to other similar systems, OCHEM is not intended to re-implement the existing tools or models but rather to invite the original authors to contribute their results, make them publicly available, share them with other users and to become members of the growing research community. Our intention is to make OCHEM a widely used platform to perform the QSPR/QSAR studies online and share it with other users on the Web. The ultimate goal of OCHEM is collecting all possible chemoinformatics tools within one simple, reliable and user-friendly resource. The OCHEM is free for web users and it is available online at http://www.ochem.eu.
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http://dx.doi.org/10.1007/s10822-011-9440-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131510PMC
June 2011

Technique for energy decomposition in the study of "receptor-ligand" complexes.

J Chem Inf Model 2009 Jun;49(6):1389-406

Chelyabinsk State Medical Academy, Pharmaceutical Chemistry, Chelyabinsk, Russian Federation 454048.

A new methodology to describe the interactions in "receptor-ligand" complexes is presented. The methodology is based on a combination of the 3D/4D QSAR BiS/MC and CoCon algorithms. The first algorithm performs the restricted docking of compounds to receptor pockets. The second determines the relationships between the bioactivity and the parameters of interactions in the "receptor-ligand" complexes, including a new formalism for estimating hydrogen bond energies.
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http://dx.doi.org/10.1021/ci800405nDOI Listing
June 2009