Exploring the inhibitory potential of novel piperidine-derivatives against main protease (Mpro) of SARS-CoV-2: A hybrid approach consisting of molecular docking, MD simulations and MMPBSA analysis.

[Display omitted] • A hybrid computational approach consisting of different computational methods is used. • Molecular electronic structures, and therapeutic potential of piperidine compounds are tested against SARS-CoV-2. • The molecular docking and MD simulations results reveal the significant therapeutic potential of designed compounds. • The MMPBSA analysis indicate that all the complexes possess good binding free energy at binding site of receptor. • ADMET analysis reveals that all eight ligands are efficient drug candidates for Mpro of SARS-CoV-2. In the current study, a hybrid computational approach consisting of different computational methods to explore the molecular electronic structures, bioactivity and therapeutic potential of piperidine compounds against SARS-CoV-2. The quantum chemical methods are used to study electronic structures of designed derivatives, molecular docking methods are used to see the most potential docking interactions for main protease (MPro) of SARS-CoV-2 while molecular dynamic and MMPBSA analyses are performed in bulk water solvation process to mimic real protein like aqueous environment and effectiveness of docked complexes. We designed and optimized piperidine derivatives from experimentally known precursor using quantum chemical methods. The UV–Visible, IR, molecular orbitals, molecular electrostatic plots, and global chemical reactivity descriptors are carried out which illustrate that the designed compounds are kinetically stable and reactive. The results of MD simulations and binding free energy revealed that all the complex systems possess adequate dynamic stability, and flexibility based on their RMSD, RMSF, radius of gyration, and hydrogen bond analysis. The computed net binding free energy (Δ G b i n d ) as calculated by MMPBSA method for the complexes showed the values of −4.29 kcal.mol−1 for P1, −5.52 kcal.mol−1 for P2, −6.12 kcal.mol−1 for P3, −6.35 kcal.mol−1 for P4, −5.19 kcal.mol−1 for P5, 3.09 kcal.mol−1 for P6, −6.78 kcal.mol−1 for P7, and −6.29 kcal.mol−1 for P8.The ADMET analysis further confirmed that none of among the designed ligands violates the Lipinski rule of five (RO5). The current comprehensive investigation predicts that all our designed compounds are recommended as prospective therapeutic drugs against Mpro of SARS-CoV-2 and it provokes the scientific community to further perform their in-vitro analysis. [ABSTRACT FROM AUTHOR]