Design, Synthesis, and Computational Studies with ADMET of Novel Cardiovascular Hybrid Drugs

Abstract

Recently the drug discovery trend has been to design hybrid drug molecules consisting of different pharmacophore groups linked together via spacers. Calcium channel blockers have an important role in the treatment of several cardiovascular diseases. The objective of the present research work is to encompass the strategic design, synthesis, and computational assessment of novel 1,4- dihydropyridine containing calcium channel blocker hybrid containing beta blocker side chain along with NO group as promoting cardiovascular agents as a viable alternative to well-established drugs like Amlodipine, Nifedipine, Felodipine, etc. In this research, we synthesized new 18 cardiovascular hybrid compounds based on structure-activity relationship properties. The 3D crystallographic structure of the calcium channel receptor (6M7H) was obtained from PDB. RCSB and used for docking study. The molecular docking studies were carried out by using the standard option Glide 5.5 in Maestro. In silico molecular docking analysis of all the synthesized compounds, AE1 to AE18, showed good docking scores and remarkable interactions with the essential amino acid residues located within the receptor's binding pocket of 6M7H. In comparison to amlodipine, AE12, AE6, AE8, AE11, AE5, AE16, and AE14 exhibit good scores as well as good binding patterns. AE12 exhibits the highest docking score of -8.455 kcal mol?1. Extensive ADMET profiling and structure–activity relationship (SAR) elucidated favorable pharmacokinetic properties and essential structural modifications influencing antihypertensive effectiveness.