#58 Design, development and in-silico evaluation of DENV protease inhibitors based on modification of Lai et al. potent molecule

Abstract

Dengue has continued to affect most of the nations of the tropical and subtropical regions of the world, it has in no way given respite in the Covid era too as cases seem to be on the rise in the year 2020 and 2021. The pandemic period has imposed a significant strain on all nations’ medical infrastructure, and the emergence of dengue and the possibility of a dengue-Covid co-infection adds to the already overburdened medical infrastructure. Hence these uncertainties call for an urgent identification of antiviral drugs against dengue. DENV NS2B-NS3 protease like the HIV and HCV protease has been identified as a potential target to arrest the viral propagation as the protease plays an important role in viral multiplication. Previously reported peptide inhibitors of DENV protease to have certain limitations as the high basic residues offer pharmacokinetic challenges due to which the molecules despite being potent protease inhibitors fail to progress forward. Small molecules offer some advantages when compared to peptide inhibitors. Here we have attempted to design small molecules based on Lai et al. (2013) reported potent molecule and perform in-silico evaluation of the designed molecule to unravel the changes in the binding affinity and predict the pharmacokinetic properties. Lai et al., potent molecule had benzoisothiazole and oxadiazole scaffolds in its architecture, we modified the molecule by incorporating certain changes which included replacement of the benzoisothiazole with an oxazole scaffold while retaining the oxadiazole moiety. The newly designed ligands were docked in the available crystal structure (PDB ID 2FOM) and the binding affinities of the reference ligand (Lai et al. molecule) and designed inhibitors were compared. Further, in-silico ADMET properties of the reference ligand and top three high scoring molecules were predicted using SwissADME and pkCSM online web server. The high affinity (-7.57) of the Lai et al. molecule could be attributed to the predicted binding involving the residues of the catalytic triad (His51, Asp75, and Ser135). Amongst the ten designed ligands F2, F4 and F9 showed comparable affinities (-6.49, -6.51 and -6.67) and it was commonly seen that important predicted interactions involved hydrogen bonding, π-π stacking interactions, and π-anion interactions with at least two residues of the catalytic triad, further, after observing the interaction pattern of the reference ligand and the designed ligand it appears that the replacement of benzoisothiazole with an oxazole scaffold preserved few interactions also it was predicted that the compounds appear to be more synthetically amenable and hence the new scaffold cloud be further explored for modification The in-silico ADMET predictions further indicates towards good pharmacokinetic properties of the top designed ligands.