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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
Menezes Spadeto, Joao Paulo [1] ; Freitas, Matheus P. [2] ; Cormanich, Rodrigo A. [1]
Total Authors: 3
Affiliation:
[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
Total Affiliations: 2
Document type: Journal article
Source: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS; OCT 2021.
Web of Science Citations: 0
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 (AU)

FAPESP's process: 20/06536-3 - Fluorinase reactive substrate analysis
Grantee:João Paulo Menezes Spadeto
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 18/03910-1 - Physicochemical studies of fluorinated organic compounds: experimental and theoretical approaches
Grantee:Rodrigo Antonio Cormanich
Support Opportunities: Research Grants - Young Investigators Grants