Protein-ligand interactions are instrumental for the structure based drug design in the human health care systems to cure problematic diseases especially cardiovascular diseases. To treat the cardiovascular disease, the Calcium Channel Blockers (CCBs) such as 1,4-dihydropyridine (DHP) derivatives have been used in a effective way. In this study, the series of nine DHP derivatives (DHP I–DHP IX) have been docked in the binding pocket of Cytochrome P450. Among these nine DHP-P450 complexes, the DHP-III [N-(4-methoxy phenyl)-3,5 dicarbethoxy-2,6-dimethyl-4-(3-nitro phenyl)-1,4-Dihydropyridine] and DHP-VI [2,6-Dimethyl-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester] exhibits lowest binding energy of −11.89 and −11.14 kcal/mol respectively, which indicates that these two molecules strongly bind to the binding pocket amino acid residues of P450 when compared with the other DHP derivatives. An analysis of hydrogen bonding interactions shows that Arg212 is essential for high affinity ligand binding. Subsequently, the C(8) atom in the DHPIII-P450 complex forms strong hydrophobic interaction with Ala3l0 while the C(8) atom in the DHPVI-P450 complex makes strong hydrogen bonding interaction with Arg212. Comparatively, the C(8) atom was not interacting with neighbouring amino acids in other DHP − P450 complexes. Further, in the DHPIII-P450 complex, the ligand makes more hydrophobic interactions with the amino acids of Ala370, Phe304, Phe213, Ile369, Met371 and Ser119. The DHP-VI molecule forms strong hydrogen bonding interactions with P450 whereas in the amlodipine-P450 complex, amlodipine reduces the better chance of making hydrogen bonding interactions due to the absence of N-phenyl ring. Thus the binding of two DHP derivatives such as DHP-III and DHP-VI are found to be higher and exhibit increased binding affinities towards Cytochrome P450. These two molecules may be considered as a drug candidate for the treatment of cardio vascular diseases as well as in vivo and in vitro studies in future.