Discovery of New Symmetrical and Asymmetrical 1,4-dihydropyridine Derivatives as Potential Antihypertensive Agents: An In silico Evaluation

Introduction: Hypertension is a worldwide problem that affects people of all ethnicities and social groups. Its mortality rate has been steadily increasing. However, several pharmacological compounds have been used to manage hypertension and related issues. Calcium Channel Blockers (CCBs) based on Dihydropyridine (DHP) are used as first-line therapy. It is well established that simple adjustments to an existing medicine's fundamental structure can considerably improve its efficacy.

Materials and methods: The purpose of this research study was to create potential antihypertensive drugs utilizing a 1,4-DHP scaffold and analyze their binding processes with different calcium channel proteins for comparative analysis, with PDB IDs 3LV3, 1T0J, and 6DAF. This study used molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) profiling to predict the binding efficacy of newly produced potential drugs, such as CCBs.

Results: The binding energy of the protein with the newly created compounds ranged between -2.6 and -7.26 kcal/mol (3LV3), -7.42 to -10.36 kcal/mol (1T0J), and -6.63 to -11.98 kcal/mol (6DAF).

Discussion: The predicted ADMET profiling yielded significant results, indicating that among the virtually prepared ligands, apart from the standard drugs amlodipine and nifedipine, ligand numbers 60 and 13 showed a favorable ADMET profile.

Conclusion: In this study, drug development efforts focused on modifying existing hypertension medications through in silico analysis. From hundreds of synthesized ligands, 19 showed optimal docking scores. ADMET profiling of these 19 ligands revealed ligands 60 and 13 to have favorable profiles. The Swiss ADME and ADMET lab 2.0 tools confirmed these findings, highlighting their potential for further development.