Design of Potent Inhibitors Targeting the Main Protease of SARS-CoV-2 Using QSAR Modeling, Molecular Docking, and Molecular Dynamics Simulations

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a serious global public health threat. The evolving strains of SARS-CoV-2 have reduced the effectiveness of vaccines. Therefore, antiviral drugs against SARS-CoV-2 are urgently needed. The main protease (Mpro) of SARS-CoV-2 is an extremely potent target due to its pivotal role in virus replication and low susceptibility to mutation. In the present study, a quantitative structure–activity relationship (QSAR) study was performed to design new molecules that might have higher inhibitory activity against SARS-CoV-2 Mpro. In this context, a set of 55 dihydrophenanthrene derivatives was used to build two 2D-QSAR models using the Monte Carlo optimization method and the Genetic Algorithm Multi-Linear Regression (GA-MLR) method. From the CORAL QSAR model outputs, the promoters responsible for the increase/decrease in inhibitory activity were extracted and interpreted. The promoters responsible for an increase in activity were added to the lead compound to design new molecules. The GA-MLR QSAR model was used to ensure the inhibitory activity of the designed molecules. For further validation, the designed molecules were subjected to molecular docking analysis and molecular dynamics simulations along with an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. The results of this study suggest that the newly designed molecules have the potential to be developed as effective drugs against SARS-CoV-2.

Identification of promising methionine aminopeptidase enzyme inhibitors: A combine study of comprehensive virtual screening and dynamics simulation study

“…In another work, 55 dihydrophenanthrene derivatives were employed to build two 2D-QSAR models. The study recognized several lead molecules against SARS-CoV-2 main protease enzyme ( Oubahmane et al, 2023 ). In short, the lead molecules identified herein are promising candidates to be evaluated in experimental studies.…”

Recent advances in chemometric modelling of inhibitors against SARS-CoV-2

“…Recently, Oubahmane's team developed 2D-QSAR models using 55 dihydrophenanthrene derivatives as potent inhibitors of SARS-CoV-2 3CLpro with Monte Carlo optimisation method and the Genetic Algorithm Multi-Linear Regression (GA-MLR) method [ 75 ]. The best Monte Carlo QSAR model ( R 2 = 0.9203 and Q 2 = 0.8508) revealed that feature fragments like “(….…”

“…There are many structural fragments in the literature that have been shown to positively contribute to the inhibitory activity of compounds [ 64 , 66 , 75 ]. Researchers can design new compounds on the basis of these substructures, and subsequently utilizing these compounds directly for docking and MD.…”

In Silico Therapeutic Study: The Next Frontier in the Fight against SARS-CoV-2 and Its Variants

“…This method involves the mathematical modeling of the relationship between physicochemical properties or molecular descriptors of compounds and their biological activities. Studies have been carried out using QSAR methods to develop phosphorus-based drugs, which have good inhibitory activity against SARS-CoV-2 proteins and their non-synonymous variants [66][67][68]. A QSAR study based on the simplified molecular-input line-entry system (SMILES) strings of 32 bicycloproline derivatives has also been applied in the discovery of COVID-19 therapeutics, with the strings applied in calculating 0D, 1D, and 2D molecular descriptors [69].…”