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

Autor(es)

Menezes Spadeto, Joao Paulo ^[1] ; Freitas, Matheus P. ^[2] ; Cormanich, Rodrigo A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Chem, Lab Expt & Theoret Organ Chem, Dept Organ Chem, POB 6154, BR-13083970 Campinas, SP - Brazil

^[2] Univ Fed Lavras, Inst Nat Sci, Dept Chem, Lavras, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS; OCT 2021.
• Citações Web of Science: 0

Resumo

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 (AU)

• Processo FAPESP: 20/06536-3 - Análise de substratos reativos da Fluorinase
• Beneficiário: João Paulo Menezes Spadeto
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 18/03910-1 - Estudos físico-químicos de compostos orgânicos fluorados: abordagens experimental e teórica
• Beneficiário: Rodrigo Antonio Cormanich
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores