Docking-Based Comparative Intermolecular Contacts Analysis as New 3-D QSAR Concept for Validating Docking Studies and in Silico Screening: NMT and GP Inhibitors as Case Studies

Abstract

The significant role played by docking algorithms in drug discovery combined with their serious pitfalls prompted us to envisage a novel concept for validating docking solutions, namely, docking-based comparative intermolecular contacts analysis (dbCICA). This novel approach is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration on the basis of its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands and vice versa. In other words, dbCICA evaluates the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models can be translated into valid pharmacophore models that can be used as 3-D search queries to mine structural databases for new bioactive compounds. dbCICA was implemented to search for new inhibitors of candida N-myristoyl transferase as potential antifungal agents and glycogen phosphorylase (GP) inhibitors as potential antidiabetic agents. The process culminated in five selective micromolar antifungal leads and nine GP inhibitory leads.