Computational Design of Copper Ligands with Controlled Metal Chelating, Pharmacokinetics, and Redox Properties for Alzheimer’s Disease

Issue title: Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America

Guest editors: K.S. Jagannatha Rao, Gabrielle B. Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny and Ricardo B. Maccioni

Article type: Research Article

Authors: Chaparro, Diego^{a; b} | Flores-Gaspar, Areli^{b; *} | Alí-Torres, Jorge^{a; *}

Affiliations: [a] Departamento de Química, Universidad Nacional de Colombia, Bogotá, Colombia | [b] Departamento de Química, Universidad Militar Nueva Granada, Cajicá, Colombia

Correspondence: [*] Correspondence to: Jorge Alí-Torres, Av. Cra 30 N 45-03, Bogotá, Colombia. Tel.: +57 1 3165000/ Ext. 10608; E-mail: jialit@unal.edu.co; Areli Flores-Gaspar, E-mail: areli.flores@unimilitar.edu.co.

Abstract: Background:Redox active metal cations, such as Cu2 +, have been related to induce amyloid plaques formation and oxidative stress, which are two of the key events in the development of Alzheimer’s disease (AD) and others metal promoted neurodegenerative diseases. In these oxidative events, standard reduction potential (SRP) is an important property especially relevant in the reactive oxygen species formation. Objective:The SRP is not usually considered for the selection of drug candidates in anti-AD treatments. In this work, we present a computational protocol for the selection of multifunctional ligands with suitable metal chelating, pharmacokinetics, and redox properties. Methods:The filtering process is based on quantum chemical calculations and the use of in silico tools. Calculations of SRP were performed by using the M06-2X density functional and the isodesmic approach. Then, a virtual screening technique (VS) was used for similar structure search. Results:Protocol application allowed the assessment of chelating, drug likeness, and redox properties of copper ligands. Those molecules showing the best features were selected as molecular scaffolds for a VS procedure in order to obtain related compounds. After applying this process, we present a list of candidates with suitable properties to prevent the redox reactions mediated by copper(II) ion. Conclusion:The protocol incorporates SRP in the filtering stage and can be effectively used to obtain a set of potential drug candidates for AD treatments.

Keywords: Alzheimer’s disease, antioxidants, computer-aided drug design, density functional theory (DFT) calculations, drug discovery, metal complexes, redox

DOI: 10.3233/JAD-200911

Journal: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S179-S193, 2021