Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand–Receptor Complexes
Ma’mon M. Hatmal, Mutasem O. Taha · Journal of Chemical Information and Modeling · 2018
We previously combined molecular dynamics (classical or simulated annealing) with ligand–receptor contacts analysis as a means to extract valid pharmacophore model(s) from single ligand–receptor complexes. However, molecular dynamics methods are computationally expensive and time-consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within a reasonable time scale. The new method is based on ligand–receptor contacts analysis following energy relaxation of a predetermined set of randomly deformed complexes generated from the targeted crystallographic structure. Ligand–receptor contacts maintained across many deformed/relaxed structures are assumed to be critical and used to guide pharmacophore development. This methodology was implemented to develop valid pharmacophore models for PI3K-γ, RENIN, and JAK1. The resulting pharmacophore models were validated by receiver operating characteristic (ROC) analysis against inhibitors extracted from the CHEMBL database. Additionally, we implemented pharmacophores extracted from PI3K-γ to search for new inhibitors from the National Cancer Institute list of compounds. The process culminated in new PI3K-γ/mTOR inhibitory leads of low micromolar IC 50 s.