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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Molecules; v. 25, n. 2 JAN 2 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 16/24524-7 - Análise estrutural e estudos de modelagem molecular para ligantes de origem natural e sintética relacionados a doenças negligenciadas
• Beneficiário: Kathia Maria Honorio
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/10118-0 - Estudo e aplicação da tecnologia eletroquímica para a análise e a degradação de interferentes endócrinos: materiais, sensores, processos e divulgação científica
• Beneficiário: Marcos Roberto de Vasconcelos Lanza
• Linha de fomento: Auxílio à Pesquisa - Temático