RESUMEN
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Ribonucleósidos , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Amidas , Antivirales/química , Microscopía por Crioelectrón , Humanos , Simulación del Acoplamiento Molecular , Nucleósidos , Polifosfatos , Pirazinas , ARN Viral , ARN Polimerasa Dependiente del ARN , Reproducción , Ribonucleósidos/farmacología , SARS-CoV-2RESUMEN
Traditional trial-and-error methods are time-consuming and inefficient, especially very unfriendly to inexperienced analysts, and are sometimes still used to select preprocessing methods or wavelength variables in near-infrared spectroscopy (NIR). To deal with this problem, a new optimization algorithm called synergy adaptive moving window algorithm based on the immune support vector machine (SA-MW-ISVM) is proposed in this paper. Following the principle of SA-MW-ISVM, the original problem of calibration model optimization is transformed into a mathematical optimization problem that can be processed by the proposed immune support vector machine regression algorithm. The main objective of this optimization problem is the calibration model performance; meanwhile, the constraint conditions include a reasonable spectral data value, spectral data preprocessing method, and calibration model parameters. A unique antibody structure and specific coding and decoding method are used to achieve collaborative optimization in NIR spectroscopy. The tests on four actual near-infrared datasets, including a group of gasoline and three groups of diesel fuels, have shown that the proposed SA-MW-ISVM algorithm can significantly improve the calibration performance and thus achieve accurate prediction results. In the case of gasoline, the SA-MW-ISVM algorithm can decrease the prediction error by 44.09% compared with the common benchmark partial least square (PLS). Meanwhile, in the case of diesel fuels, the SA-MW-ISVM algorithm can decrease the prediction error of cetane number, freezing temperature, and viscosity by 9.99%, 28.69%, and 43.85%, respectively, compared with the PLS. The powerful prediction performance of the SA-MW-ISVM algorithm makes it an ideal tool for modeling near-infrared spectral data or other related application fields.