An electronic point of view on the inhibition of ALK-5 by bioactive candidates related to cancer

Author(s)

Almeida, Michell O. ^{[1, 2]} ; Faria, Sergio H. D. M. ^{[3, 4]} ; Honorio, Kathia M. ^{[2, 5]}

Affiliation

^[1] Univ Sao Paulo, Inst Quim Sao Carlos, Ave Joao Dagnone 1100, BR-13563120 Sao Carlos, SP - Brazil

^[2] Univ Fed ABC UFABC, Ctr Ciencias Nat & Humanas, Rua Santa Adelia 166, BR-09210170 Santo Andre, SP - Brazil

^[3] Univ Estadual Campinas UNICAMP, Inst Quim, Rua Josue de Castro 126, Cidade Univ, BR-13083861 Campinas, SP - Brazil

^[4] Univ Paulista UNIP, Av Comendador Enzo Ferrari 280, BR-13045770 Campinas, SP - Brazil

^[5] Univ Sao Paulo Ciencias & Humanidades, Escola Artes, Av Arlindo Bettio 1000, BR-03828000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: THEORETICAL CHEMISTRY ACCOUNTS; v. 139, n. 5 MAY 6 2020.
• Web of Science Citations: 0

Abstract

Cancer is a very complex disorder, and it is urgent to find new ways to treat it. This study aims to evaluate the inhibition mechanism of ALK-5 (target related to breast cancer) from an electronic point of view. Computational simulations (QM/MM, NBO, QTAIM) were performed, and the ONIOM method (B3LYP/cc-pVDZ:UFF) was used to obtain the optimized geometries of the studied systems. The NBO analyses indicated that the most important electron transfer occurs between LP N (inhibitor 1) and BD{*} O-H (Tyr249) orbitals (Delta E-2 = 11.89 kcal/mol). The weakest interaction occurs between the LP N (inhibitor 4) and BD{*} N-H (His283) orbitals (Delta E-2 = 0.81 kcal/mol). The QTAIM analyses suggested that the most active inhibitors perform a greater number of hydrogen bonds with the major residues. Therefore, quantum mechanics methods proved to be important to better understand the inhibition of ALK-5, as well as helping the design of new inhibitors. (AU)

• FAPESP's process: 14/27189-9 - Theoretical study of the interaction between bioactive ligands and TGF-² receptor type 1 (ALK-5) using methods of molecular modeling
• Grantee: Michell de Oliveira Almeida
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/24524-7 - STRUCTURAL ANALYSIS AND MOLECULAR MODELING STUDIES FOR NATURAL AND SYNTHETIC LIGANTS RELATED TO NEGLECTED DISEASES
• Grantee: Kathia Maria Honorio
• Support type: Regular Research Grants
• FAPESP's process: 17/10118-0 - Study and application of electrochemical technology for the analysis and degradation of endocrine interferents: materials, sensors, processes and scientific dissemination
• Grantee: Marcos Roberto de Vasconcelos Lanza
• Support type: Research Projects - Thematic Grants