Harnessing the structural determinants amenable for polypharmacological behavior of 7D against Sirt1 and CXCR3.

Discovery of polypharmacological agents, inhibiting targets, either the same or diverse pathways, is an emerging paradigm in drug discovery. Designing such a candidate is challenging due to the lack of structural and dynamical consensus determinants of interacting partners. We identified a dual target inhibitor, 7D (mono-peptide of benzimidazole), a dengue antiviral lead against host proteins (Sirt1 and CXCR3) to underpin polypharmacological features. Targeting host proteins represents a compelling antiviral strategy as the modulation of host-regulated pathways can suppress dengue virus replication without directly engaging viral proteins, thereby minimizing the risk of resistance. Genesis of 7D discovery, critical determinants were identified for its rational designing to achieve Sirt1 selectivity. Focusing on the antiviral target, CXCR3 was explored via virtual screening of the in-house compound library. Among identified candidates, 7D appeared to be a potential hit, confirmed via in vitro and in vivo means, leading the basis to underscore the determinants responsible for polypharmacological behavior, paving a way for feature-based designing of such candidates.