Structure-Based Virtual Screening, Molecular Dynamics and Binding Free Energy Calculations of Hit Candidates as ALK-5 Inhibitors

Author(s)

Araujo, Sheila C. ^[1] ; Maltarollo, Vinicius G. ^[2] ; Almeida, Michell O. ^[3] ; Ferreira, Leonardo L. G. ^[4] ; Andricopulo, Adriano D. ^[4] ; Honorio, Kathia M. ^{[1, 5]}

Affiliation

^[1] Fed Univ ABC, CCNH, BR-09210580 Santo Andre, SP - Brazil

^[2] Univ Fed Minas Gerais, Fac Pharm, Dept Pharmaceut Prod, BR-31270901 Belo Horizonte, MG - Brazil

^[3] Univ Sao Paulo, IQSC, BR-13563120 Sao Carlos, SP - Brazil

^[4] Univ Sao Paulo, Phys Inst Sao Carlos, Lab Med & Computat Chem, BR-13563120 Sao Carlos, SP - Brazil

^[5] Univ Sao Paulo, EACH, BR-03828000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Molecules; v. 25, n. 2 JAN 2 2020.
• Web of Science Citations: 0

Abstract

Activin-like kinase 5 (ALK-5) is involved in the physiopathology of several conditions, such as pancreatic carcinoma, cervical cancer and liver hepatoma. Cellular events that are landmarks of tumorigenesis, such as loss of cell polarity and acquisition of motile properties and mesenchymal phenotype, are associated to deregulated ALK-5 signaling. ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. Due to their ability to impair cell migration, invasion and metastasis, ALK-5 inhibitors have been explored as worthwhile hits as anticancer agents. This work reports the development of a structure-based virtual screening (SBVS) protocol aimed to prospect promising hits for further studies as novel ALK-5 inhibitors. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors. (AU)

• 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 Opportunities: Regular Research Grants
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• 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 Opportunities: Research Projects - Thematic Grants