Pharmacophore-Model-Based Drug Repurposing for the Identification of the Potential Inhibitors Targeting the...

Dengue virus (DENV) is the causative agent of DENV infection. To tackle DENV infection, the development of therapeutic molecules as direct-acting antivirals (DAAs) has been demonstrated as a truly effective approach. Among various DENV drug targets, non-structural protein 5 (NS5)-a highly conserved protein among the family Flaviviridae-carries the RNA-dependent RNA polymerase (DENV^RdRp) domain at the C-terminal, and its "N-pocket" allosteric site is widely considered for anti-DENV drug development. Therefore, in this study, we developed a pharmacophore model by utilising 41 known inhibitors of the DENV^RdRp domain, and performed model screening against the FDA's approved drug database for drug repurposing against DENV^RdRp. Herein, drugs complying with the pharmacophore hypothesis were further processed through standard-precision (SP) and extra-precision (XP) docking scores (DSs) and binding pose refinement based on MM/GBSA binding energy (BE) calculations. This resulted in the identification of four potential potent drugs: (i) desmopressin (DS: -10.52, BE: -69.77 kcal/mol), (ii) rutin (DS: -13.43, BE: -67.06 kcal/mol), (iii) lypressin (DS: -9.84, BE: -67.65 kcal/mol), and (iv) lanreotide (DS: -8.72, BE: -64.7 kcal/mol). The selected drugs exhibited relevant interactions with the allosteric N-pocket of DENV^RdRp, including priming-loop and entry-point residues (i.e., R729, R737, K800, and E802). Furthermore, 100 ns explicit-solvent molecular dynamics simulations and end-point binding free energy assessments support the considerable stability and free energy of the selected drugs in the targeted allosteric pocket of DENV^RdRp. Hence, these four drugs, repurposed as potent inhibitors of the allosteric site of DENV^RdRp, are recommended for further validation using experimental assays.