Fluorinated dihydropyridines as candidates to block L-type voltage-dependent calcium channels

Abstract

Voltage-gated calcium (Ca_v) channels malfunction may lead to Alzheimer's and cardiovascular disorders, thus a critical protein target for drug development and treatment against several diseases. Indeed, dihydropyridines (DHPs) as nifedipine and amlodipine are top-selling pharmaceuticals and, respectively, the 121st and 5th most prescribed drugs in the United States that have been used as successful selective blockers for L-type Ca2+ channels (LCC) and may be helpful model structures to compare with new DHP analogs. In this context, we have performed a structure-based drug design (SBDD) study of several fluorinated DHPs by using homology modeling, molecular docking, quantitative structure activity relationship (QSAR) and molecular dynamics calculations. Such approaches combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) interaction energy results and screening of ADMET (absorption, distribution, metabolism, excretion and toxicity) properties indicate that all ligands in this study are potential new candidates to be tested experimentally for inhibition of LCC and may have higher affinities than the commonly used drugs, being convenient synthetic routes proposed for 11–16, which are among the ligands that showed the best theoretical results concerning LCC inhibition. Furthermore, the ligand interactions with the binding site were carefully examined using the topological noncovalent interactions (NCI) method, which highlighted specifically responsible amino acid residues that increase the spontaneity of the new proposed DHP ligands.

Communicated by Ramaswamy H. Sarma

Keywords:

• Organofluorine compounds
• Hantzsch adducts
• QSAR
• molecular docking
• molecular dynamics

Acknowledgements

The authors are grateful to FAPESP and FAEPEX for the financial support of this research. The authors also thank FAPESP (#2018/03910-1) and FAEPEX (#2466/20) for the fellowships to RAC and FAPESP for a scholarship to JPMS (#2020/06536-3). The authors are also thankful to CAPES (funding code: 001), CNPq (#301371/2017-2), and FAPEMIG for financial support of this research. CENAPAD-SP, CESUP and SDumont computational resources are also gratefully acknowledged.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript.