Design, In Silico Screening, Synthesis, Characterisation and DFT-based Electronic Properties of Dihydropyridine-based Molecule as L-type Calcium Channel Blocker

Abstract

Objective: The objectives of this study are first to design potential antihypertensive drugs based on the DHP scaffold, secondly, to analyse drug-likeness properties of the ligands and investigate their molecular mechanisms of binding to the model protein Cav1.2 and finally to synthesise the best ligand. Methods: Due to the lack of 3D structures for human Cav1.2, the protein structure was modelled using a homology modelling approach. A protein-ligand complex's strength and binding interaction were investigated using molecular docking and molecular dynamics techniques. DFT-based electronic properties of the ligands were calculated using the M06-2X/ def2-TZVP level of theory. The SwissADME website was used to study the ADMET properties. Results: In this study, a series of DHP compounds (19 compounds) were properly designed to act as calcium channel blockers. Among these compounds, compound 16 showed excellent binding scores (-11.6 kcal/mol). This compound was synthesised with good yield and characterised. To assess the structural features of the synthesised molecule quantum chemical calculations were performed. Conclusion: Based on molecular docking, molecular dynamics simulations, and drug-likeness properties of compound 16 can be used as a potential calcium channel blocker.