PAMAM–guanylthiourea conjugates mask furin's substrate binding site: mechanistic insights from molecular docking and molecular dynamics studies assist the design of potential furin inhibitors

Abstract

Furin, a subtilisin-like proprotein convertase human enzyme, is promising as a single therapeutic target for several viral manifestations. Hence, understanding the molecular mechanisms that are key to putative furin action would lead to the systemic development of specific and potent antivirals. To guide the rational design of potential furin inhibitors through a detailed mechanistic analysis of specific molecular interactions, we conducted in silico screening of an in-house library of a zero generation poly(amidoamine) dendrimer (G0 PAMAM) and its guanylthiourea derivatives (PAMAM–GTU). Molecular docking suggested substituent-guided tailored interactions and molecular dynamics simulation unveiled PAMAM–GTU's binding with furin's catalytic triad, whereas single arm GTU substitution influenced the interactions with Asp153, His194 and Ser368. The substituent effect on the binding free energy of dendrimer-furin interaction was assessed by MM/GBSA. One-step synthesis of PAMAM–GTU was achieved using a versatile thiocarbamoyl amidine transfer strategy. For the first time, a basic alumina column was optimized as an economically viable purification platform for PAMAM–GTUs, which were characterized by ¹H- and ¹³C -NMR and HRMS (ESI) techniques.