RESUMEN
The coronavirus disease 19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global health crisis with millions of confirmed cases and related deaths. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and presents an attractive target for drug development. Despite the approval of some drugs, the search for effective treatments continues. In this study, we systematically evaluated 342 holo-crystal structures of Mpro to identify optimal conformations for structure-based virtual screening (SBVS). Our analysis revealed limited structural flexibility among the structures. Three docking programs, AutoDock Vina, rDock, and Glide were employed to assess the efficiency of virtual screening, revealing diverse performances across selected Mpro structures. We found that the structures 5RHE, 7DDC, and 7DPU (PDB Ids) consistently displayed the lowest EF, AUC, and BEDROCK scores. Furthermore, these structures demonstrated the worst pose prediction results in all docking programs. Two structural differences contribute to variations in docking performance: the absence of the S1 subsite in 7DDC and 7DPU, and the presence of a subpocket in the S2 subsite of 7DDC, 7DPU, and 5RHE. These findings underscore the importance of selecting appropriate Mpro conformations for SBVS, providing valuable insights for advancing drug discovery efforts.
Asunto(s)
Proteasas 3C de Coronavirus , Simulación del Acoplamiento Molecular , SARS-CoV-2 , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Humanos , Conformación Proteica , Cristalografía por Rayos X , Antivirales/química , Antivirales/farmacología , Benchmarking , COVID-19/virología , Unión ProteicaRESUMEN
In this research, we employed a deep reinforcement learning (RL)-based molecule design platform to generate a diverse set of compounds targeting the neuraminidase (NA) of influenza A and B viruses. A total of 60,291 compounds were generated, of which 86.5 % displayed superior physicochemical properties compared to oseltamivir. After narrowing down the selection through computational filters, nine compounds with non-sialic acid-like structures were selected for in vitro experiments. We identified two compounds, DS-22-inf-009 and DS-22-inf-021 that effectively inhibited the NAs of both influenza A and B viruses (IAV and IBV), including H275Y mutant strains at low micromolar concentrations. Molecular dynamics simulations revealed a similar pattern of interaction with amino acid residues as oseltamivir. In cell-based assays, DS-22-inf-009 and DS-22-inf-021 inhibited IAV and IBV in a dose-dependent manner with EC50 values ranging from 0.29 µM to 2.31 µM. Furthermore, animal experiments showed that both DS-22-inf-009 and DS-22-inf-021 exerted antiviral activity in mice, conferring 65 % and 85 % protection from IAV (H1N1 pdm09), and 65 % and 100 % protection from IBV (Yamagata lineage), respectively. Thus, these findings demonstrate the potential of RL to generate compounds with promising antiviral properties.
Asunto(s)
Subtipo H1N1 del Virus de la Influenza A , Virus de la Influenza A , Gripe Humana , Animales , Ratones , Humanos , Oseltamivir/farmacología , Oseltamivir/uso terapéutico , Antivirales/farmacología , Antivirales/uso terapéutico , Inteligencia Artificial , Proteínas Virales , Farmacorresistencia Viral , Virus de la Influenza B , NeuraminidasaRESUMEN
Influenza virus remains a major public health challenge due to its high morbidity and mortality and seasonal surge. Although antiviral drugs against the influenza virus are widely used as a first-line defense, the virus undergoes rapid genetic changes, resulting in the emergence of drug-resistant strains. Thus, new antiviral drugs that can outwit resistant strains are of significant importance. Herein, we used deep reinforcement learning (RL) algorithm to design new chemical entities (NCEs) that are able to bind to the native and H275Y mutant (oseltamivir-resistant) neuraminidases (NAs) of influenza A virus with better binding energy than oseltamivir. We generated more than 66211 NCEs, which were prioritized based on the filtering rules, structural alerts, and synthetic accessibility. Then, 18 NCEs with better MM/PBSA scores than oseltamivir were further analyzed in molecular dynamics (MD) simulations conducted for 100 ns. The MD experiments showed that 8 NCEs formed very stable complexes with the binding pocket of both native and H275Y mutant NAs of H1N1. Furthermore, most NCEs demonstrated much better binding affinity to group 2 (N2, N3, and N9) and influenza B virus NAs than oseltamivir. Although all 8 NCEs have non-sialic acid-like structures, they showed a similar binding mode as oseltamivir, indicating that it is possible to find new scaffolds with better binding and antiviral properties than sialic acid-like inhibitors. In conclusion, we have designed potential compounds as antiviral candidates for further synthesis and testing against wild and mutant influenza virus.Communicated by Ramaswamy H. Sarma.