Pharmacophore-guided fragment-based design of novel mammalian target of rapamycin inhibitors: extra precision docking, fingerprint-based 2D and atom-based 3D-QSAR modelling

Abstract

Rapamycin and their derivatives known as rapalogs were the first-generation mTOR inhibitors which interacted with mTORC1 but not with the mTORC2 protein. Second-generation inhibitors could bind with both and showed excellent anti-proliferative activity. Our aim was to design novel mTOR inhibitors which could bind at both the allosteric and the kinase site. The FRB domain is present in both the mTORC1 and mTORC2 protein complexes. We have employed e-pharmacophore-guided fragment-based design to develop novel mTOR inhibitors. The affinity of designed molecules at both the sites was analysed using molecular docking in extra precision mode. The atom-based 3D-QSAR model was developed to predict the activity while the fingerprint-based 2D-QSAR model was employed to refine an identified hit as potent dual mTOR inhibitor. Ligand ASK23 showed a docking score of −15.452 kcal/mol at the allosteric site (PDB ID 5GPG) while ASK38 showed a docking score of −11.535 kcal/mol at the kinase site (PDB ID 4JT6). Ligand ASK12 showed binding energy of −106.23 kcal/mol at the allosteric site. Refined molecule ASK12a from ASK12 showed the highest predicted activity (pIC50: 6.512). The stability of the best hits and receptor complex was analysed using molecular dynamics simulation studies. Herein we report five potential mTOR dual inhibitors based on the predicted activity, drug-likeness analysis and off-target effects. To the best of our knowledge, this is the first report on pharmacophore-guided fragment-based drug design for mTOR inhibitors. This design strategy can be used for the rational drug design against other proteins for which only apo-structures are available. Communicated by Ramaswamy H. Sarma