In silico De Novo Discovery of Novel Target-specific Drug-like Bidentate Inhibitors of PTP 1B

Abstract

Background: Protein tyrosine phosphatase 1B (PTP 1B) is a recognized legitimate target for type 2 diabetes and obesity, collectively designated as ‘diabesity’, even though first-in-class inhibitor is still awaited. The main cause behind the unachieved target selectivity of investigated inhibitors is the high degree of sharing of structural homology between PTP 1B and other members of the PTP family. Objective: The present work aimed to discover target-specific inhibitors of PTP 1B with bidentate binding features on both the allosteric and active sites. Materials and Methods: We have implicated the amalgamated de novo designing, ADMET screening, and molecular docking simulations to discover novel drug-like allosteric inhibitors of PTP 1B. The LEA3D de novo designing platform was used to design novel thiazolidinediones (TZDs) from scratch in the core of the target on the strict constraints of defined molecular properties of drug-likeness. Molecular modelling and geometry optimization were done using the ChemOffice package. The druglikeness/ ADMET screening was performed using the TSAR package based on Lipinski’s filter. Molegro Virtual Docker (MVD) was used for the prediction of binding cavities in the target, estimation of ligandtarget binding affinities as well as mode of binding interactions. Results and Discussion: Novel TZDs (Molecules 1-8) were de novo designed successfully as drug-like target-specific inhibitors of PTP 1B. The interaction pattern and the energy contribution of ligand (Etotal, Eintra, Epair) and target (Epair) supported that the generated TZDs showed bidentate inhibition. Conclusion: The discovered TZDs can be developed as novel target-specific allosteric inhibitors of PTP 1B after the accomplishment of synthetic and pre-clinical interventions.