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Exploring the Mechanism of Covalent Inhibition: Simulating the Binding Free Energy of α-Ketoamide Inhibitors of the Main Protease of SARS-CoV-2.

ABSTRACT: The development of reliable ways of predicting the binding free energies of covalent inhibitors is a challenge for computer-aided drug design. Such development is important, for example, in the fight against the SARS-CoV-2 virus, in which covalent inhibitors can provide a promising tool for blocking M^pro, the main protease of the virus. This work develops a reliable and practical protocol for evaluating the binding free energy of covalent inhibitors. Our protocol presents a major advance over other approaches that do not consider the chemical contribution of the binding free energy. Our strategy combines the empirical valence bond method for evaluating the reaction energy profile and the PDLD/S-LRA/β method for evaluating the noncovalent part of the binding process. This protocol has been used in the calculations of the binding free energy of an α-ketoamide inhibitor of M^pro. Encouragingly, our approach reproduces the observed binding free energy. Our study of covalent inhibitors of cysteine proteases indicates that in the choice of an effective warhead it is crucial to focus on the exothermicity of the point on the free energy surface of a peptide cleavage that connects the acylation and deacylation steps. Overall, we believe that our approach should provide a powerful and effective method for in silico design of covalent drugs.

SUBMITTER: Mondal D

PROVIDER: S-EPMC7688048 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.

Project description:The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

| S-EPMC7164518 | biostudies-literature

An insight into the interaction between α-ketoamide- based inhibitor and coronavirus main protease: A detailed in silico study.

Project description:The search for therapeutic drugs that can neutralize the effects of COVID-2019 (SARS-CoV-2) infection is the main focus of current research. The coronavirus main protease (Mpro) is an attractive target for anti-coronavirus drug design. Further, α-ketoamide is proved to be very effective as a reversible covalent-inhibitor against cysteine proteases. Herein, we report on the non-covalent to the covalent adduct formation mechanism of α-ketoamide-based inhibitor with the enzyme active site amino acids by QM/SQM model (QM = quantum mechanical, SQM = semi-empirical QM). To uncover the mechanism, we focused on two approaches: a concerted and a stepwise fashion. The concerted pathway proceeds via deprotonation of the thiol of cysteine (here, Cys145 SγH) and simultaneous reversible nucleophilic attack of sulfur onto the α-ketoamide warhead. In this work, we propose three plausible concerted pathways. On the contrary, in a traditional two-stage pathway, the first step is proton transfer from Cys145 SγH to His41 Nδ forming an ion pair, and consecutively, in the second step, the thiolate ion attacks the α-keto group to form a thiohemiketal. In this reaction, we find that the stability of the tetrahedral intermediate oxyanion/hydroxyl group plays an important role. Moreover, as the α-keto group has two faces Si or Re for the nucleophilic attack, we considered both possibilities of attack leading to S- and R-thiohemiketal. We computed the structural, electronic, and energetic parameters of all stationary points including transition states via ONIOM and pure DFT method. Additionally, to characterize covalent, weak noncovalent interaction (NCI) and hydrogen-bonds, we applied NCI-reduced density gradient (NCI-RDG) methods along with Bader's Quantum Theory of Atoms-in-Molecules (QTAIM) and natural bonding orbital (NBO) analysis.

| S-EPMC7695570 | biostudies-literature

COVID-19: In silico identification of potent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2.

Project description:The COVID-19 has been creating a global crisis, causing countless deaths and unbearable panic. Despite the progress made in the development of the vaccine, there is an urge need for the discovery of antivirals that may better work at different stages of SARS-CoV-2 reproduction. The main protease (Mpro) of the SARS-CoV-2 is a crucial therapeutic target due to its critical function in virus replication. The α-ketoamide derivatives represent an important class of inhibitors against the Mpro of the SARS-CoV. While there is 99% sequence similarity between SARS-CoV and SARS-CoV-2 main proteases, anti-SARS-CoV compounds may have a huge demonstration's prospect of their effectiveness against the SARS-CoV-2. In this study, we applied various computational approaches to investigate the inhibition potency of novel designed α-ketoamide-based compounds. In this regard, a set of 21 α-ketoamides was employed to construct a QSAR model, using the genetic algorithm-multiple linear regression (GA-MLR), as well as a pharmacophore fit model. Based on the GA-MLR model, 713 new designed molecules were reduced to 150 promising hits, which were later subject to the established pharmacophore fit model. Among the 150 compounds, the best selected compounds (3 hits) with greater pharmacophore fit score were further studied via molecular docking, molecular dynamic simulations along with the Absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Our approach revealed that the three hit compounds could serve as potential inhibitors against the SARS-CoV-2 Mpro target.

| S-EPMC8205609 | biostudies-literature

Exploring Structural Mechanism of COVID-19 Treatment with Glutathione as a Potential Peptide Inhibitor to the Main Protease: Molecular Dynamics Simulation and MM/PBSA Free Energy Calculations Study.

Project description:The 2019-novel coronavirus has unfolded everywhere in the world and obliged a billion human beings in open confinement, whereas many treatments, and vaccines have been proposed towards this pandemic. The main protease (Mpro) is an attractive drug target due to the fact that it is the essential protein for virus invasion. This research tests in silico the effect of five vitamins towards Mpro, by employing molecular docking (MD), molecular dynamics simulation (MDS) with molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) studies. To achieve this work, we have applied some software's as Autodock Vina, Discovery Studio Visualizer, APBS, and GROMACS. The inhibitors used were decided entirely on the basis of their importance in the production of red blood cells that prevent anemia, in lymphocyte immune system responses, in the regulation of reactive oxygen species production, such as tocopherol (vitamin E), thiamine (vitamin B1), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), biotin (vitamin B7), and glutathione (GSH). The best inhibitor pose established at the highest repetition ratio (RR) and the minimal affinity energy value (MEV), then the best selected inhibitor was considered to MDS. The results indicate that GSH is the leading inhibitor model among the other tested vitamins in the active site of Mpro with a RR value of 94% and MEV of - 5.5 kcal/mol, its RMSD, RMSF, Rg, and hydrogen bonds show stability with Mpro. Furthermore, thiamine, biotin, and tocopherol are viewed as satisfying inhibitors to Mpro, but pyridoxine was observed as the weakest inhibitor. Based on our result, we could recommend the usage of glutathione and vitamin B family as a supportive strategy for feasible remedy of COVID-19 virus.

| S-EPMC8777181 | biostudies-literature

Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations.

Project description:The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.

| S-EPMC8430524 | biostudies-literature

Inhibition of SARS-CoV-2 main protease 3CL<sup>pro</sup> by means of α-ketoamide and pyridone-containing pharmaceuticals using in silico molecular docking.

Project description:The coronavirus disease infections (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) have been emerging in the entire world. Therefore, it is necessary to find out potential therapeutic pharmaceuticals for this disease. This study investigates the inhibitory effect of the 3-chymotrypsin-like protease of SARS-CoV-2 (3CLpro) using pharmaceuticals containing α-ketoamide group and pyridone ring based on molecular docking. Of these, eight pharmaceuticals approved by US-Food and Drug Administration have shown good contact with the catalytic residues of 3CLpro. They are telaprevir, temsirolimus, pimecrolimus, aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide. Their binding affinity score ranged from -5.6 to -7.4 kcal/mol. Hydrogen bonds were observed and reported. To the knowledge, this study report for the first time a compound that could be binding to ALA285, the new residue resulting from genetic modification of 3CLpro of SARS-CoV-2 that has increased its catalytic activity 3.6-fold compared with its predecessor 3CLpro of SARS-CoV. It is recommended that telaprevir, and pyridone-containing pharmaceuticals including aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide be repurposed for COVID-19 treatment after suitable validation and clinical trials.

| S-EPMC7347502 | biostudies-literature

Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.

Project description:Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (MPro ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure-based techniques against MPro itself.

| S-EPMC10364469 | biostudies-literature

Assessing potential inhibitors of SARS-CoV-2 main protease from available drugs using free energy perturbation simulations.

Project description:The main protease (Mpro) of the novel coronavirus SARS-CoV-2, which has caused the COVID-19 pandemic, is responsible for the maturation of its key proteins. Thus, inhibiting SARS-CoV-2 Mpro could prevent SARS-CoV-2 from multiplying. Because new inhibitors require thorough validation, repurposing current drugs could help reduce the validation process. Many recent studies used molecular docking to screen large databases for potential inhibitors of SARS-CoV-2 Mpro. However, molecular docking does not consider molecular dynamics and thus can be prone to error. In this work, we developed a protocol using free energy perturbation (FEP) to assess the potential inhibitors of SARS-CoV-2 Mpro. First, we validated both molecular docking and FEP on a set of 11 inhibitors of SARS-CoV-2 Mpro with experimentally determined inhibitory data. The experimentally deduced binding free energy exhibits significantly stronger correlation with that predicted by FEP (R = 0.94 ± 0.04) than with that predicted by molecular docking (R = 0.82 ± 0.08). This result clearly shows that FEP is the most accurate method available to predict the binding affinity of SARS-CoV-2 Mpro + ligand complexes. We subsequently used FEP to validate the top 33 compounds screened with molecular docking from the ZINC15 database. Thirteen of these compounds were predicted to bind strongly to SARS-CoV-2 Mpro, most of which are currently used as drugs for various diseases in humans. Notably, delamanid, an anti-tuberculosis drug, was predicted to inhibit SARS-CoV-2 Mpro in the nanomolar range. Because both COVID-19 and tuberculosis are lung diseases, delamanid has higher probability to be suitable for treating COVID-19 than other predicted compounds. Analysis of the complexes of SARS-CoV-2 Mpro and the top inhibitors revealed the key residues involved in the binding, including the catalytic dyad His14 and Cys145, which is consistent with the structural studies reported recently.

| S-EPMC9119318 | biostudies-literature

Selective covalent targeting of SARS-CoV-2 main protease by enantiopure chlorofluoroacetamide.

Project description:The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) is a promising target for COVID-19 treatment. Here, we report an irreversible SARS-CoV-2 Mpro inhibitor possessing chlorofluoroacetamide (CFA) as a warhead for the covalent modification of Mpro. Ugi multicomponent reaction using chlorofluoroacetic acid enabled the rapid synthesis of dipeptidic CFA derivatives that identified 18 as a potent inhibitor of SARS-CoV-2 Mpro. Among the four stereoisomers, (R,R)-18 exhibited a markedly higher inhibitory activity against Mpro than the other isomers. Reaction kinetics and computational docking studies suggest that the R configuration of the CFA warhead is crucial for the rapid covalent inhibition of Mpro. Our findings highlight the prominent influence of the CFA chirality on the covalent modification of proteinous cysteines and provide the basis for improving the potency and selectivity of CFA-based covalent inhibitors.

| S-EPMC8905997 | biostudies-literature

Interaction of the prototypical α-ketoamide inhibitor with the SARS-CoV-2 main protease active site in silico: Molecular dynamic simulations highlight the stability of the ligand-protein complex.

Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes an illness known as COVID-19, which has been declared a global pandemic with over 2 million confirmed cases and 137,000 deaths in 185 countries and regions at the time of writing (16 April 2020), over a quarter of these cases being in the United States. In the absence of a vaccine, or an approved effective therapeutic, there is an intense interest in repositioning available drugs or designing small molecule antivirals. In this context, in silico modelling has proven to be an invaluable tool. An important target is the SARS-CoV-2 main protease (Mpro), involved in processing translated viral proteins. Peptidomimetic α-ketoamides represent prototypical inhibitors of Mpro. A recent attempt at designing a compound with enhanced pharmacokinetic properties has resulted in the synthesis and evaluation of the α-ketoamide 13b analogue. Here, we performed molecular docking and molecular dynamics simulations to further characterize the interaction of α-ketoamide 13b with the active site of the SARS-CoV-2 Mpro. We included the widely used antibiotic, amoxicillin, for comparison. Our findings indicate that α-ketoamide 13b binds more tightly (predicted GlideScore = -8.7 and -9.2 kcal/mol for protomers A and B, respectively), to the protease active site compared to amoxicillin (-5.0 and -4.8 kcal/mol). Further, molecular dynamics simulations highlight the stability of the interaction of the α-ketoamide 13b ligand with the SARS-CoV-2 Mpro (ΔG = -25.2 and -22.3 kcal/mol for protomers A and B). In contrast, amoxicillin interacts unfavourably with the protease (ΔG = +32.8 kcal/mol for protomer A), with unbinding events observed in several independent simulations. Overall, our findings are consistent with those previously observed, and highlight the need to further explore the α-ketoamides as potential antivirals for this ongoing COVID-19 pandemic.

| S-EPMC7253975 | biostudies-literature

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