Annotation of the results obtained in 2022
(1) Continuing the work of the previous stages of the project to study the mechanism of enhancing catalytic activity in the enzymatic domain of adenylate cyclase (AC) of the bPAC optogenetic system upon irradiation of the photoreceptor BLUF domain, the structures of the dimeric complex (BLUF-AC)2 were constructed for various variants of the monomer composition. Based on the results of classical molecular dynamics calculations using the NAMD program with the CHARMM36 force field, we compared the dynamic properties of complexes that include the dark or light (photoactivated) state of the BLUF domain, as well as variants of the AC catalytic domain with or without the presence or absence of the substrate adenosine triphosphate in the active site. Visualization, processing of trajectory calculations, and dynamic network analysis, which can be used to trace the amino acid residues of the polypeptide chain that transmit the signal after excitation of the photosensitive center in the BLUF domain to the active center in the catalytic domain, were carried out using the VMD program. According to the results of extended molecular dynamics calculations of the optogenetic system - the dimeric protein bPAC, it was shown that the characteristics of the monomers are different in the process of evolution over time. Differences are observed for geometry parameters, in particular, for the angles between the photoreceptor domain and the catalytic domain in each monomer. Dynamic network analysis shows that signal transduction pathways from the photoreceptor domain to the catalytic center in light-irradiated states differ from dark states. Signaling pathways are also affected by which monomer is in the light or dark state. Kulakova A.M., Khrenova M.G., Nemukhin A.V. “Non-equivalence of monomers in the dimeric structure of photoregulated adenylate cyclase”, Biophysica, 2022, 67, no. 6, 1101-1108; DOI: 10.31857/S0006302922060072. (2) Work on modeling the enzymatic activity of guanosine triphosphate-binding proteins (GTPases) is an essential part of the research planned in the project. At the stage of 2022, the problem of the role of a point replacement of the Gly12 amino acid residue, which is not formally included in the active center of the small GTPases, the Ras enzyme, on the catalytic activity of the Ras-GAP protein complex, was solved. Modeling the properties of the Ras enzyme in a complex with the GAP acceleration protein is an important task for biomedical research, since the replacement of the amino acid residue of glycine at position 12 with valine (G12V) in the human Ras protein is one of the most common among cancer patients, despite the fact that according to X-ray diffraction analysis of the Ras(GTP)-GAP complex, the amino acid residue at position 12 is located away from the active center. To elucidate the reason for the slowdown of the catalytic activity of G12VRas-GAP compared to the native variant of the Ras protein, an analysis of the reaction conformations of enzyme-substrate (ES) complexes was used, carried out by the method of molecular dynamics with the potentials of quantum mechanics/molecular mechanics (QM/MM MD). More specifically, the ratio of reactive to non-reactive ES complexes for the native Ras-GAP system and the G12VRas-GAP variant was compared. Appropriate geometry parameters were chosen as criteria for classifying conformations as reactive ones. In calculations by the QM(PBE0-D3/6-31G**)/MM(CHARMM) MD method using the TeraChem and NAMD programs, the phosphate groups of GTP, amino acid residues Gly/Val12, Gly13, Lys16, Ser17, Thr35, Ile36, Ala59, Gly60, Gln61 and a magnesium cation from Ras, three water molecules and an Arg789 side chain from GAP were assigned to quantum subsystems, giving rise to a total of 112 atoms, not counting the hydrogen atoms added at the interface between the QM and MM subsystems. It has been shown that the arrangement of molecular groups in the active site of the enzyme changes significantly when the glycine residue in position 12 is replaced by valine (G12V), which leads to a decrease in the fraction of reactive conformations in the GTP hydrolysis reaction. An important methodological result of the work is the conclusion that it is necessary to use atom-centered basis sets and hybrid functionals when calculating potentials in the QM(DFT)/MM MD method using the TeraChem-NAMD programs. Comparison with the results of previous calculations of a lower level of accuracy with the CP2K program using a mixed basis of plane waves and Gaussian functions and the BLYP generalized gradient functional shows that the use of a technique of a lower level of accuracy leads to noticeable distortions in the calculated distributions of ensembles of enzyme-substrate complexes. Khrenova M.G., Polyakov I.V., Nemukhin A.V. "Molecular dynamics of enzyme-substrate complexes in guanosine triphosphate-binding proteins", Khimicheskaya Fizika, 2022, 41 (6), 66-72; DOI: 10.31857/S0207401X22060061. (3) Studies have been carried out on the chemical reaction mechanism of covalent inhibition by carmofur of the main protease MPro of the SARS-CoV-2 virus. The MPro enzyme belongs to the class of cysteine ​​proteases, the covalent inhibition of which can be achieved by chemical addition of a suitable molecule to the Cys145 cysteine ​​residue of the catalytic site. The ability of the carmofur molecule to form a covalently bonded adduct with MPro was shown experimentally, but the mechanism of the chemical reaction was not previously studied. Based on the results of modeling by QM/MM methods, the elementary stages of the interaction reaction between carmofur and the catalytic cysteine ​​residue MPro were characterized for the first time. It was shown that the first step is the transfer of a proton from Cys145 to another member of the catalytic dyad His41 with the formation of an reaction intermediate with the Cys-/His+ ion pair. The second stage (from the intermediate with an ion pair to the product) determines the rate of the reaction. The general view of the reaction energy profile is consistent with the experimental result on the possibility of covalent inhibition of the main protease of the SARS-CoV-2 virus by carmofur - the activation barrier corresponds to the reaction conditions at room temperatures, and the energy effect of the reaction is consistent with the formation of a stable covalent adduct. Comparison of the results of calculations of reaction energy profiles by the QM/MM method using the NWChem and Q-Chem programs showed that in order to ensure the reproducibility of the results of calculations by the QM/MM method, users of software packages need to provide significantly more details about the data entered into the programs when publishing materials than is usually the case. For qualitative assessments of reaction mechanisms, as well as for predicting promising covalent inhibitors of enzymes, the detected problems in the implementation of the QM/MM method are not critical. Giudetti G., Polyakov I., Grigorenko B.L., Faraji S., Nemukhin A.V., Krylov A.I. «How Reproducible Are QM/MM Simulations? Lessons from Computational Studies of the Covalent Inhibition of the SARS-CoV 2 Main Protease by Carmofur», Journal of Chemical Theory and Computation (Q1, IF = 6,006), 2022, 18, 5056-5067; DOI: 10.1021/acs.jctc.2c00286. (4) In addition to the study the reaction of MPro with carmofur, planned for 2022, the QM/MM calculations of the mechanisms of chemical reactions of covalent inhibition of MPro by other compounds, nirmatrelvir and two modified versions of the known non-covalent inhibitor X77, were also performed. It was shown that the reactions of these three compounds with the catalytic amino acid residue Cys145 of the enzyme proceed by different mechanisms. According to the results obtained, all the considered compounds should effectively inhibit the main protease of the SARS-CoV-2 virus. Grigorenko B.L., Polyakov I., Giudetti G., Faraji S., Krylov A.I., Nemukhin A.V. «Simulations of the Covalent Inhibition of the SARS-CoV-2 Main Protease: Four Compounds and Three Reaction Mechanisms», ChemRxiv, Published August 2022. DOI: 10.26434/chemrxiv-2022-8lr3v).

 

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Annotation of the results obtained in 2019
For the first time, a model of the optogenetic system based on the dimeric bacterial photoactivated adenylate cyclase bPAC was constructed. The model system includes two photoreceptor flavin-containing BLUF domains and two catalytic domains of the adenylate cyclase (AC) enzyme. Simulations were initiated by a crystallographic structure in the apo-form of the enzyme, i.e., without the substrate (adenosine triphosphate (ATP)) molecules in the catalytic domains. In our work, a full-atom three-dimensional model of the bPAC protein complex was constructed by the methods of molecular mechanics and molecular dynamics, the ATP molecules were deposited into the active sites of the AC catalytic domains of both monomers, and a bright form with the imidic tautomer of the critical amino acid glutamine residue in the chromophore-containing domain BLUF domains was constructed. According to the calculation results, the inequivalence of monomers in all three model systems was shown. Upon the excitation, the most noticeable changes were noticed in the apo form of the enzyme and in the environment of cofactors. The results are published in the article: Kulakova A.M., Khrenova M.G., Nemukhin A.V. “The structure and dynamics of photoregulated adenylate cyclase,” Russian Chemistry Bulletin, Chemical Series, 2019, No. 11, pp. 1991-1996. (http://www.russchembull.ru/rus/index.php3?id=293&idi=4979&state=&rc=0&idp=0&action=showfull&type=%CF%EE%EB%ED%FB%E5%20%F1%F2%E0%F2%FC%E8). According to the results of calculations by the methods of molecular dynamics and quantum mechanics/molecular mechanics (QM/MM), the mechanism of the enzymatic reaction of the conversion of adenosine triphosphate to the cyclic adenosine monophosphate (ATP → cAMP) catalyzed by mammalian adenylate cyclase is investigated. A model molecular system was constructed, for which several structures of the enzyme-substrate complex were determined. The latter differed in substrate conformations and coordination shells of magnesium cations. It is shown that several variants of the reaction mechanism discussed in the literature, which are initiated by some of these structures, correspond to the pathways with the unrealistically high energy barriers. The structure of the enzyme-substrate complex has been selected, which corresponds to a single-step reaction mechanism with the energy profile completely consistent with the experimental rate constants. The simulations show the key role of the solvation shells of the magnesium cations in this reaction mechanism, as well as the role of “proton wires”, i.e., the oriented chains of hydrogen-bonded molecular groups, including, in particular, water molecules in the coordination sphere of the magnesium ion. The results are published in the preprint of the article: Grigorenko B.L., Polyakov I.V., Nemukhin A.V. “Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires”, ChemRxiv, DOI: 10.26434/chemrxiv.9209180.v1 (https://chemrxiv.org/articles/Mechanisms_of_ATP_to_cAMP_Conversion_Catalyzed_by_the_Mammalian_Adenylyl_Cyclase_A_Role_of_Magnesium_Coordination_Shells_and_Proton_Wires/9209180). By the results of quantum mechanics/molecular mechanics (QM/MM) calculations, the vibrational spectra were predicted for two reaction intermediates in the hydrolysis reaction of guanosine triphosphate (GTP) by the Ras • GAP complex. The natural Ras protein and the protein with the 15N labelled side chain of Gln61 amino acid residue were considered. It is shown that three vibrational bands of the model system fall into the region of wave numbers 1620-1750 cm –1. Two of them refer to the coupled vibrations of the C = O and NH2 groups of the amide form Gln61 in the structure of the enzyme-substrate complex, and they are slightly sensitive to isotopic substitution. The third band, assigned to the C = N vibration of the imide form of Gln61, is shifted up to 20 cm-1 during isotopic substitution, which should be recorded in experimental studies of enzymatic catalysis by using time-resolved IR spectroscopy. This predicted effect will allow an experimental verification of the mechanism revealed in simulations of this important biochemical reaction. The results are presented in the article: Grigorenko B.L., Nemukhin A.V. “Theoretical vibrational spectra of reaction intermediates in the active center of guanosine triphosphate-binding proteins,” Russian Journal of Physical Chemistry, 2020, accepted for publication. According to the results of calculations by quantum mechanics/molecular mechanics (QM/MM), the reaction mechanism for the recovery of the active site of acetylcholinesterase poisoned by an organophosphorus agent with the help of a new reactivator was revealed. The results are published in the article: Lushchekina S.V., et al. «6-methyluracil as peripheral site ligand-hydroxamic acid conjugates: Reactivation for paraoxon-inhibited acetylcholinesterase», European Journal of Medicinal Chemistry, 2020, 185, 111787; DOI: 10.1016/j.ejmech.2019.111787 (URL https://www.sciencedirect.com/science/article/pii/S0223523419309390?via%3Dihub).

 

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Annotation of the results obtained in 2020
The mechanism of the enzymatic reaction of the conversion of adenosine triphosphate to the cyclic adenosine monophosphate (ATP → cAMP) catalyzed by adenylate cyclases is developed based on the results of calculations by the methods of molecular dynamics (MD), quantum mechanics/molecular mechanics (QM/MM) and MD methods with QM/MM potentials. Calculations by the QM (DFT (PBE0-D3/6-31G *))/MM (AMBER) method lead to the conclusion that in the active site of the mammalian adenylate cyclase mAC the reaction proceeds according to the following one-step mechanism with an activation barrier of ~ 15 kcal/mol, namely, proton transfer H3' on the side chain of aspartic acid through a water molecule is accompanied by a nucleophilic attack by O3' of the PA atom and cleavage of the PA- O3A bond. The results are published in [Grigorenko B.L., Polyakov I.V., Nemukhin A.V. “Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires”, Journal of Physical Chemistry B (IF=2,857, Q1), V.124(3), P.451-460 (2020); DOI: 10.1021/acs.jpcb.9b07349]. Calculations of the Gibbs energy profile by the QM(DFT(ωB97X-D3/6-31G **))/MM (CHARMM) MD method for this reaction in the catalytic domains of the bacterial photoactivated adenylate cyclase bPAC led to similar conclusions about the mechanism [Khrenova M.G., Kulakova A.M., Nemukhin A.V. “Light-Induced Change of Arginine Conformation Modulates the Rate of ATP to cAMP Conversion in the Optogenetic System bPAC”, archive of open access preprints in chemistry (https://chemrxiv.org) ChemRxiv, DOI: 10.26434/chemrxiv.13139723.v1]. The mechanism of enzymatic activity enhancement in the bPAC catalytic domains upon photoexcitation of BLUF domains has been revealed. Structures of the bPAC four-domain complexes in dark and light forms were built. The light form is obtained from the dark one by replacement of the amide functional group of the side chain of Gln49 in BLUF domains with an imide one. Next, we performed a dynamic network analysis of bPAC complexes using classical molecular dynamics methods, and identified the signal transmission pathways from BLUF domains to AC domains upon photoexcitation. The most important result is the conclusion about a conformational change of the Arg278 amino acid side chain located near the ATP molecule. Calculations of the Gibbs energy profile of the ATP → cAMP reaction by the QM (DFT (ωB97X-D3 / 6-31G **)) / MM (CHARMM) MD method in the dark and light states lead to the conclusion that the conformational changes in the structure of the enzyme-substrate complex, caused by the transition of bPAC from the dark form (ES-DS) to the light form (ES-LS) upon photoexcitation, explain the observed effect of acceleration of the reaction under illumination of the optogenetic complex. Qualitatively, the reaction mechanism in the light state does not change, the shape of the energy profile is also similar to that obtained for the dark state, but the activation barrier decreases from 15 to 9 kca/mol. For a model system with a point mutation Tyr7Phe in the photoreceptor BLUF domain (with the amide form of Gln49), it was shown that in this case both conformations of Arg278 are present in approximately equal ratio, which is consistent with the experimentally observed intermediate catalytic activity of the bPAC Tyr7Phe complex. [Khrenova M.G., Kulakova A.M., Nemukhin A.V. “Light-Induced Change of Arginine Conformation Modulates the Rate of ATP to cAMP Conversion in the Optogenetic System bPAC”, ChemRxiv Open Access Preprint Archive (https://chemrxiv.org) ChemRxiv, DOI: 10.26434 / chemrxiv.13139723.v1] . Molecular modeling methods, including molecular mechanics (MM), molecular dynamics (MD), and quantum mechanics/molecular mechanics (QM/MM) methods, were used to characterize the mechanism of covalent inhibition of the oncogenic variant of guanosine triphosphate-binding protein (GTPase) KRasG12C by ARS-853 and characterize the channels of non-covalent inhibition of KRasG12C by ARS-853 and ARS-1620. The cycle of activation/deactivation of GTPases of the Ras superfamily is based on switching between two states of the system - with a molecule of either guanosine triphosphate (GTP) or guanosine diphosphate (GDP) included in the protein matrix. The transition from the GTP-containing form occurs during the GTP hydrolysis reaction. Intensive experimental searches for the suppression of activation (i.e., the conversion of the inactive GDP-containing form of the KRasG12C mutant into the active GTP-containing form) led to the design of allosteric inhibitors from the ARS group, of which the ARS-1620 and ARS-853 compounds are the most promising in modern clinical trials. The ARS-853 compound molecule consists of a reactive part (warhead) responsible for covalent attachment of the enzyme to the Cys12 amino acid residue, groups responsible for efficient molecular coupling of the compound to a protein (fragments for a hydrophobic pocket), and a connecting fragment (linker). Model systems of the KRasG12C-GDP complexes with ARS-853 and ARS-1620 were constructed based on the coordinates of heavy atoms of crystal structures using molecular modeling methods. Molecular dynamics methods were used to calculate the free energy profile for ARS-853 dissociation from the binding pocket on the protein surface. The QM (PBE0-D3/cc-pVDZ) /MM method was used to calculate the profile of the chemical reaction of the ARS-853 interaction with KRasG12C-GDP. Based on all these calculations, the full Gibbs free energy profile was constructed for the enzyme inhibition reaction by the ARS-853 compound and the entire set of kinetic constants was determined. The dependence of the observed reaction rate on the concentration of ARS-853 was estimated by numerically solving the differential equations of chemical kinetics. The obtained simulation results correlate well with the experimental data. The results were published [Khrenova M.G., Kulakova A.M., Nemukhin A.V. “Proof of concept for poor inhibitor binding and efficient formation of covalent adducts of KRASG12C and ARS compounds”, Organic & Biomolecular Chemistry (IF = 3.564, Q1) 2020, 18, 3069-3081; DOI: 10.1039 / d0ob00071j]. The compound ARS-1620, from the same series as ARS-853, differs in fragments of the linker and hydrophobic region. The non-covalent interaction of ARS-1620 with KRasG12C-GDP was studied by molecular dynamics and molecular docking methods, which made it possible to estimate the dissociation constant of the KRasG12C-GDP-ARS-1620 complex. The results are published [Kulakova А.М., Zakharova Т.М., MUlashkin F.D., Terekhova E.O., Khrenova M.G. «Estimation of dissociation constant of ARS-1620 complex with KRasG12C protein by molecular modeling», Moscow University Research Bulletin, Series 2, Chemistry, 2020, V. 61,#№2, P. 8-12].

 

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Annotation of the results obtained in 2021
All studies carried out in 2021 are completely consistent with the declared purposes of the project, namely, “the development and application of simulation tools to model structures and properties of biomolecular systems, including enzymes and optogenetic components, using quantum chemistry and molecular dynamics calculations”. (1) The studies of enzymes performing the activation/deactivation cycles of GTPases, planned on the year 2021, have been accomplished. We report the results of calculations of the Gibbs energy profiles of the guanosine triphosphate (GTP) hydrolysis by the Arl3-RP2 protein complex using molecular dynamics (MD) simulations with ab initio type QM/MM potentials, which allow us to formulated the corresponding reaction mechanism of a complex bimolecular process. A small GTPase Arl3 catalyzing the GTP → GDP reaction in complex with the activating protein RP2 constitute an essential part of the human vision cycle. To simulate the reaction mechanism, a model system is constructed by motifs of the crystal structure of the Arl3-RP2 complexed with a substrate analog. After selection of reaction coordinates, energy profiles for elementary steps along the reaction pathway GTP + H2O → GDP + Pi are computed using the umbrella sampling and umbrella integration procedures. QM/MM MD calculations are carried out interfacing the molecular dynamics program NAMD and the quantum chemistry program TeraChem. Ab initio type QM(DFT)/MM potentials are computed with atom-centered basis sets 6-31G** and two hybrid functionals (PBE0-D3 and ωB97x-D3) of the density functional theory describing a large QM subsystem. Results of these simulations of the reaction mechanism are compared to those obtained with QM/MM calculations on the potential energy surface using similar description of the QM part. We find that both approaches, QM/MM and QM/MM MD, support the mechanism of GTP hydrolysis by GTPases, according to which the catalytic glutamine side chain (Gln71, in this system) actively participates in the reaction. Both approaches distinguish two parts of the reaction: the cleavage of the phosphorus-oxygen bond in GTP coupled with formation of Pi, and the enzyme regeneration. Newly performed QM/MM MD simulations confirmed the profile predicted in QM/MM minimum energy calculations, called here the pathway-I, and corrected its relief at the first elementary step from the enzyme-substrate complex. The QM/MM MD simulations also revealed another mechanism at the part of enzyme regeneration leading to the pathway-II. The pathway-II is better consistent with the experimental kinetic data of the wild-type complex Arl3-RP2, whereas the pathway-I explains the role of the mutation Glu138Gly in RP2 slowing down the hydrolysis rate. The results are published: Khrenova M.G., Kulakova A.M., Nemukhin A.V. «Light-Induced Change of Arginine Conformation Modulates the Rate of Adenosine Triphosphate to Cyclic Adenosine Monophosphate Conversion in the Optogenetic System Containing Photoactivated Adenylyl Cyclase», Journal of Chemical Information and Modeling (American Chemical Society, Q1, IF=4,956), 2021, 61, 1215−1225; DOI: 10.1021/acs.jcim.0c01308 (published: March 08, 2021) https://pubs.acs.org/doi/abs/10.1021/acs.jcim.0c01308 (2) At the stage of 2021, calculations of the energy profiles of individual elementary stages of chemical reactions taking place in the Venus66azF protein, a potential optogenetic system, were performed. This study was not previously planned, and the QM/MM simulations were carried out in response to the suggestion of the research team from the University of Cardiff (Wales), in which the protein was prepared and characterized experimentally. In the experiments, a protein of the type of green fluorescent protein was synthesized, in which, in place of the traditional amino acid residue Tyr66, there is a residue of an unnatural amino acid p-azido-L-phenylalanine. In this variant (Venus66azF), the protein is colorless, but after UV irradiation, as a result of a cascade of chemical reactions (the stage of chromophore oxidation occurs, and a nitrogen molecule is split off from the azide), a chromophore capable of yellow fluorescence is formed. In the course of the experiments, a wealth of information was obtained about the chemical reactions and the corresponding reaction intermediates in this system. In particular, the structure of the protein was presumably trapped before the stage of oxidation, i.e. with an oxygen molecule in the chromophore-containing region. We performed calculations by the QM/MM method for a series of elementary steps from a system with molecular oxygen near an immature chromophore to an intermediate with a hydroxyperoxyl group covalently linked to the chromophore. For each intermediate, the optical excitation spectra were also calculated and compared with experimental data. The resulting set of experimental and theoretical data made it possible to formulate certain conclusions about the mechanism of the oxidation stage during the formation of chromophores of a wide class of fluorescent proteins - the most important markers in living systems. The results obtained in several research teams are published: Auhim H.S., Grigorenko B.L., Harris T.K., Aksakal O.E., Polyakov I.V., Berry C., Gomes G.P., Alabugin I.V., Rizkallah P.J., Nemukhin A.V., Jones D.D. "Stalling chromophore synthesis of the fluorescent protein Venus reveals the molecular basis of the final oxidation step", Chemical Science (Royal Society of Chemistry, Q1, IF=9.825), 2021, 12, 7735-7745; DOI: 10.1039/d0sc06693a (published: April, 2021). https://pubs.rsc.org/en/content/articlelanding/2021/sc/d0sc06693a (3) Studies have been carried out on the mechanism of the chemical reaction of covalent inhibition of the main protease of the SARS-CoV-2 virus. Molecular modeling methods were applied to design a potential covalent inhibitor and the profile of the chemical reaction of the inhibitor attachment to the catalytic cysteine residue of the enzyme was calculated using the QM/MM method. The relevance of work on the study of the components of the coronavirus does not require justification. The main protease of SARS-CoV-2, namely, an enzyme of the cysteine protease family called Mpro, is considered as a possible target for a therapeutic treatment of COVID-19. A new direction in the search for covalent Mpro inhibitors is the proposal to use reagents containing the aromatic groups capable of attaching to a cysteine residue by the reaction of nucleophilic aromatic substitution SNAr. Based on the results of supercomputer molecular modeling of the reaction of the interaction of a compound built from a benzoisothiazolone (BZT) fragment and 5-fluoro-6-nitro-pyrimidine-2,4 (1H, 3H) -dione (FNP) with the main protease Mpro of the SARS-CoV- 2, it is concluded that this reaction with a limiting energy barrier of no more than 9 kcal/mol is possible, and the resulting covalently bound adduct can irreversibly block the functioning of the enzyme, and, consequently, of the virus. The reaction proceeds by the mechanism of nucleophilic aromatic substitution SNAr with the formation of a stable intermediate, the Meisenheimer complex. An analysis of the structures and the electron density in the region of the intermediate shows that in this complex, the bond with the leaving group is broken and a covalent bond is formed between the reactants. The obtained results, which give an idea of the molecular mechanism of inhibition of the main protease of the SARS-CoV-2 virus, form the basis for the development of new inhibitors of cysteine proteases, including the Mpro protease. The results of the work were reported at the XXVII Symposium "Bioinformatics and Computer Design of Drugs" (Moscow, April 5-7, 2021, Nemukhin A.V. - plenary report) and published - Nemukhin A.V., Grigorenko B.L., Lushchekina S. V., Varfolomeev S.D. "Supercomputer modeling of covalent inhibition of the main protease of the SARS-CoV-2 virus", Russian Chemical Bulletin, 2021, No. 11, 2084 - 2089 (published: October 2021).

 

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