Identificación de nuevos inhibidores de la enzima acetohidroxiácido sintasa (AHAS) de Candida albicans mediante cribado virtual de fragmentos

Abstract

The enzyme acetohydroxyacid synthase (EC 2.2.1.6., AHAS), is considered a new therapeutic target for the control of invasive fungal infections (IFIs) due to its crucial activity in the biosynthesis of essential amino acids (BCAAs) in the fungal agents that cause these diseases. The herbicides of the sulfonylurea and triazolopyrimidine families are some of the most promising compounds for the development of an IFIs treatment by the inhibition of AHAS. These project focuses on the identification of possible new inhibitors of the AHAS enzyme in the yeast, Candida albicans, using virtual fragment screening. The parental structures used for virtual screening are the central fragments of the herbicides Chlorimuron ethyl (CE) and Metosulam (MT), which were selected by a structural analysis of its binding mode to AHAS. This analysis yielded the fragments FRAG1 and FRAG2, based on CE, and FRAGMT, based on MT. Fragment screening was performed on the ACFIS2.0 server, a tool that provided approximately 250. The analysis of calculated Gibbs free energy, the ligand -CaAHAS binding mode and ADME properties allowed the best molecules to be identified. Using this method, it was determined that ligands KIN102, KIN97 KIN20, (generated from FRAG1); PAD271, KIN192, PAD181 (generated from FRAG2), PAD281, PAD165 and PAD180 (generated from FRAGMT) present a higher affinity than CE and MT when binding C. albicans AHAS. Also, these ligands exhibited binding modes analogous to their parental herbicides; therefore, the ligands could act as possible inhibitors of AHAS and potentially become drugs for the treatment of IFIs.