Designing of next-generation dihydropyridine-based calcium channel blockers: An in silico study
Sujoy Karmakar, Hriday Kumar Basak, Uttam Paswan, Arun Kumar Pramanik, Abhik Chatterjee.
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Hypertension is a most prevalent problem in this world and it is seen among all races and all social classes. The trend of mortality rate has been increasing day by day. But different drug molecules have been utilised to control hypertension and associated problems. Dihydropyridine (DHP)-based drugs, which are calcium channel blockers (CCBs), are prescribed as a first-line option. It is well documented that minor changes to the core scaffold of an existing medicine can significantly improve its efficacy. The goal of this research was to develop prospective antihypertensive medicines using a 1,4-DHP scaffold and investigate their binding mechanisms with calcium channel proteins having Protein Data Bank IDs 5KLS and 5KLB. The binding efficiency of newly created prospective compounds such as calcium CCBs was predicted using molecular docking and molecular dynamics (MD) simulation analyses in this study. The binding energy of the proteins with the newly created compounds ranged between -6.86 and −10.05 kcal/mol (Autodock 4.2). Compound 10 with the proteins had the lowest binding energies of −10.05 and −9.99 kcal/mol, which were lower than the commonly used drugs, amlodipine and nifedipine. The molecular mechanics/generalized born surface area calculations based on dynamics yielded good results, and MD simulation indicates that the complexes are stable.
Key words: Keywords: Calcium channel blockers; anti-hypertensive drug; molecular docking; molecular dynamics simulation.