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

Abstract

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.

Protein characteristics substantially influence the propensity of activity cliffs among kinase inhibitors

“…Overall, based on this information, it is challenging to draw definitive conclusions regarding how these specific tripeptide sequences influence the ACs phenomenon. Nevertheless, as pioneers in proposing the protein-related nature of the AC phenomenon, we hypothesized in earlier publications that the presence of potent AC twin members induces substantial, entropy-driven conformational changes in the target protein 24 , 25 . This hypothesis finds support in experimental evidence.…”

“…This supposition is in line with our recently presented theory, which states that the binding of potent AC members results in large, entropically driven conformational alterations in the target protein, which in turn reveal hidden attractive features within the binding site. These "new" interaction sites offer extra enthalpic binding contributions 24 , 25 .…”

In silico screening of chalcones and flavonoids as potential inhibitors against yellow head virus 3C-like protease

“…According to previous studies about potentials of flavonoid and chalcone as viral protease inhibitors, as well as their low toxicity and bioavailable nature, a set of flavonoids and chalcones from our database was considered for identification of bioactive drug candidates for inhibition of YHV major protease, YHV 3CL pro , using computational approaches ( Abudayah et al, 2022 ; Al-Sha’er, Basheer & Taha, 2023 ). The YHV 3CL pro model predicted by deep learning-based structural modeling was used to identify potential candidates of chalcones and flavonoids by molecular docking, drug-likeness prediction, and molecular dynamics (MD) simulations.…”