title: Reduced density gradient as a novel approach for estimating QSAR descriptors, and its application to 1, 4-dihydropyridine derivatives with potential antihypertensive effects.
abstract: The relationship between the chemical structure and biological activity (log IC50) of 40 derivatives of 1,4-dihydropyridines (DHPs) was studied using density functional theory (DFT) and multiple linear regression analysis methods. With the aim of improving the quantitative structure-activity relationship (QSAR) model, the reduced density gradient s( r) of the optimized equilibrium geometries was used as a descriptor to include weak non-covalent interactions. The QSAR model highlights the correlation between the log IC50with highest molecular orbital energy (EHOMO), molecular volume (V), partition coefficient (log P), non-covalent interactions NCI(H4-G) and the dual descriptor [Δf(r)]. The model yielded values of R2=79.57 and Q2=69.67 that were validated with the next four internal analytical validations DK=0.076, DQ=-0.006, RP=0.056, and RN=0.000, and the external validation Q2boot=64.26. The QSAR model found can be used to estimate biological activity with high reliability in new compounds based on a DHP series. Graphical abstract The good correlation between the log IC50with the NCI (H4-G) estimated by the reduced density gradient approach of the DHP derivatives.
authors.affiliation: Área Académica de Química, Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Hidalgo, km. 4.5 Carretera Pachuca-Tulancingo, Ciudad del Conocimiento, C.P. 42184, Mineral de la Reforma, Hidalgo, Mexico.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Jardínez
authors.affiliation: Departamento de Química, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, C.P. 07360, México, D.F., Mexico.
authors.forename: Alberto
authors.initials: A
authors.lastname: Vela
authors.affiliation: Área Académica de Química, Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Hidalgo, km. 4.5 Carretera Pachuca-Tulancingo, Ciudad del Conocimiento, C.P. 42184, Mineral de la Reforma, Hidalgo, Mexico. jcruz@uaeh.edu.mx.
authors.forename: Julián
authors.initials: J
authors.lastname: Cruz-Borbolla
authors.affiliation: Departamento de Química, Centro de Investigación y de Estudios Avanzados (Cinvestav), Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco, C.P. 07360, México, D.F., Mexico.
authors.forename: Rodrigo J
authors.initials: RJ
authors.lastname: Alvarez-Mendez
authors.affiliation: Área Académica de Química, Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Hidalgo, km. 4.5 Carretera Pachuca-Tulancingo, Ciudad del Conocimiento, C.P. 42184, Mineral de la Reforma, Hidalgo, Mexico.
authors.forename: José G
authors.initials: JG
authors.lastname: Alvarado-Rodríguez
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory
chemical_list: D000959:Antihypertensive Agents; D004095:Dihydropyridines
keywords: 1,4-dihydropyridine; Density functional theory calculation; QSAR; Reduced density gradient