ESTRATEGIA DE CRIBADO VIRTUAL BASADO EN ESTRUCTURAS APLICADA A LA BÚSQUEDA DE NUEVOS AGENTES MODULADORES DEL CANAL DE PROTONES hHv1

MARÍA VIRGINIA CHAULET; MELISA E. GANTNER; MANUEL A. LLANOS; CLARA VENTURA; VERÓNICA MILESI; LUCIANA GAVERNET

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2023

SAIC-SAB-AAFE-AACyTAL

The human voltage-gated proton channel (hHv1) is a highly selective ion channel that plays a fundamental role in various physiological processes such as innate and adaptive immunity, insulin secretion, and sperm capacitation. Recently we have demonstrated that ATP exerts an activating effect on hHV1, mainly mediated through the interaction with the ATP phosphate groups.With the aim of finding new modulatory agents through the novel ATP binding site, a structure-based virtual screening strategy was developed. First, a database defined as “ATP-like compounds” was built. For this purpose, the ATP scaffold was used as the query structure in Pubmed and GoogleScholar for literature searching and the 70% ATP -and ADP- similarity structure searching was conducted on the ZINC15 database. Then, molecules that present 3 or 2 phosphate groups were selected. Secondly, different hHv1 conformations were sampled to adequately represent the ATP binding site. Four target conformations were extracted from the production results of several Gaussian accelerated molecular dynamics simulations of our dimeric homology model of the channel, with and without ATP. The binding site volume and druggability score calculated from FPocket and DoGSiteScorer software were considered for the target conformation selection. Finally, docking simulations with AutoDock Vina were run over the ATP-like database of 601 compounds in each of the 4 channel conformations. 68 compounds with better docking score than ATP -and ADP- in at least 2 conformations were visually inspected, selecting 5 candidates with similar interactions to those observed for ATP. All of them will be evaluated in vitro on the hHv1 channel expressed in HEK293 cells by the patch-clamp technique. Finding new ATP site modulators would increase the actual understanding of the physiological and pathophysiological characteristics of the channel, and would provide new ATP-related structures with therapeutic potential.