Molecular dynamics simulation, 3D-pharmacophore and scaffold hopping analysis in the design of multi-target drugs to inhibit potential targets of COVID-19.

SARS-CoV-2 has posed serious threat to the health and has inflicted huge costs in the world. Discovering potent compounds is a critical step to inhibit coronavirus. 3CLpro and RdRp are the most conserved targets associated with COVID-19. In this study, three-dimensional pharmacophore modeling, scaffold hopping, molecular docking, structure-based virtual screening, QSAR-based ADMET predictions and molecular dynamics analysis were used to identify inhibitors for these targets. Binding free energies estimated by molecular docking for each ligand in different binding sites of RdRp were used to predict the active site. Previously reported active 3CLpro and RdRp inhibitors were used to build a pharmacophore model to develop different scaffolds. Structure-based simulations and pharmacophore modeling based on Hip Hop algorithm converged in a state that suggest hydrogen bond acceptor and donor features have a critical role in the two binding sites. Further validations indicated that the best pharmacophore model has fairly good correlation values compared with approved inhibitors. Structure-based simulation results approved that GLu166 and Gln189 in 3CLpro and Lys551 and Glu811 in RdRp, are critical residues for dual activities. Ten compounds were extracted from pharmacophore-based virtual screening in six databases. The results, gained by repurposing approach, suggest the effectiveness of these ten compounds with different scaffolds as possible inhibitors of the two targets. Some quinoline-based hybrid derivatives also were designed. QSAR descriptors plot predicted that the scaffolds have had accepted pharmacokinetic profiles. Multiple molecular dynamics simulations in 100 ns and MM/PBSA studies of some reference inhibitors and the novel compounds in complex with both targets demonstrated stable complexes and confirmed the interaction modes. Based on different computational methods, COVID-19 multi-target inhibitors are proposed.