Pharmacophore Modeling of Targets Infested with Activity Cliffs via Molecular Dynamics Simulation Coupled with QSAR and Comparison with other Pharmacophore Generation Methods: KDR as Case Study.

Activity cliffs (ACs) are defined as pairs of structurally similar compounds with large difference in their potencies against certain biotarget. We recently proposed that potent AC members induce significant entropically-driven conformational modifications of the target that unveil additional binding interactions, while their weakly-potent counterparts are enthalpically-driven binders with little influence on the protein target. We herein propose to extract pharmacophores for ACs-infested target(s) from molecular dynamics (MD) frames of purely "enthalpic" potent binder(s) complexed within the particular target. Genetic function algorithm/machine learning (GFA/ML) can then be employed to search for the best possible combination of MD pharmacophore(s) capable of explaining bioactivity variations within a list of inhibitors. We compared the performance of this approach with established ligand-based and structure-based methods. Kinase inserts domain receptor (KDR) was used as a case study. KDR plays a crucial role in angiogenic signalling and its inhibitors have been approved in cancer treatment. Interestingly, GFA/ML selected, MD-based, pharmacophores were of comparable performances to ligand-based and structure-based pharmacophores. The resulting pharmacophores and QSAR models were used to capture hits from the national cancer institute list of compounds. The most active hit showed anti-KDR IC50 of 2.76 µM.