Busca in silico de novos protó1pos moleculares para inibição da proteína cinase c iota explorando o desenho de líderes baseado em fragmentos

Abstract

Fragment-based lead design paradigm is a recent and prolific strategy in medicinal chemistry. Over the last decade, seven molecules from this approach have become approved drugs for the chemotherapy of pernicious cancers. In silico protocols, particularly molecular docking simulations, have contributed decisively to the success of some of these workflows, and have undoubtedly added greater advantages to the rational design of new ligands based on fragments. Protein kinase c iota (PKCι) is a biomarker implicated in various human dysfunctions, and has been receiving considerable attention for the development of new inhibitors. The crystallographic structures reported for this kinase corroborate the ATP binding pocket as one of the main binding sites for small molecules. Preliminarily, close visual inspection of this pocket suggested that important hotspots were unexploited in the binding mode established with the submicromolar inhibitor AFU601, cocrystallized in the PDB ID: 6ILZ structure. The rational design of new virtual inhibitors, starting from a central fragment containing the 7-azaindole moiety, has enabled the optimized exploitation of these hotspots, and provided more exergonic interactions, with significant improvements in binding energy and affinity. In total, 592 novel ligands had their physicochemical and biological properties predicted by different computational tools. In addition to the pharmacodynamic aspect, the pharmacokinetic profile of these compounds was investigated in the virtual environment. The selectivity of the best molecules for PKCι was evaluated in silico against other kinases of the human kinome, and these ligands exhibiting the best set of drug-like properties were analyzed in predictive tests of synthetic accessibility and feasibility. The most promising compounds were iteratively enhanced in subsequent docking-driven structural optimization steps, and their satisfactory results encourage the chemical synthesis of physical samples for biological assays in experimental models of PKCι-dependent diseases.