In silico identification of noncompetitive inhibitors targeting an uncharacterized allosteric site of falcipain-2

Autor(es)

Hernandez Gonzalez, Jorge Enrique ^{[1, 2, 3]} ; Salas-Sarduy, Emir ^[4] ; Hernandez Alvarez, Lilian ^[1] ; Barreto Gomes, Diego Enry ^{[2, 5]} ; Pascutti, Pedro Geraldo ^[2] ; Oostenbrink, Chris ^[3] ; Leite, Vitor B. P. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista Julio Mesquita Filho UNESP, Inst Biociencias Letras & Ciencias Exatas, Dept Fis, Rua Cristovao Colombo 2265, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[2] Univ Fed Rio de Janeiro, UFRJ, Inst Biofis Carlos Chagas Filho, Lab Modelagem & Dinam Mol, Ave Carlos Chagas Filho, 373, CCS Bloco D, Sala 30, BR-21941902 Rio De Janeiro, RJ - Brazil

^[3] Univ Nat Resources & Life Sci BOKU, Dept Mat Sci & Proc Engn, Inst Mol Modeling & Simulat, Muthgasse 18, A-1190 Vienna - Austria

^[4] Univ Nacl San Martin, CONICET, Inst Invest Biotecnol Dr Rodolfo Ugalde, San Martin, Buenos Aires - Argentina

^[5] Univ Fed Juiz De Fora UFJF, Inst Ciencias Exatas, Rua Jose Lourenco Kelmer S-N, Campus Univ, BR-36036900 Juiz De Fora, MG - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Computer-Aided Molecular Design; v. 35, n. 10, p. 1067-1079, OCT 2021.
• Citações Web of Science: 0

Resumo

Falcipain-2 (FP-2) is a Plasmodium falciparum hemoglobinase widely targeted in the search for antimalarials. FP-2 can be allosterically modulated by various noncompetitive inhibitors that have been serendipitously identified. Moreover, the crystal structures of two inhibitors bound to an allosteric site, termed site 6, of the homolog enzyme human cathepsin K (hCatK) suggest that the equivalent region in FP-2 might play a similar role. Here, we conduct the rational identification of FP-2 inhibitors through virtual screenings (VS) of compounds into several pocket-like conformations of site 6, sampled during molecular dynamics (MD) simulations of the free enzyme. Two noncompetitive inhibitors, ZINC03225317 and ZINC72290660, were confirmed using in vitro enzymatic assays and their poses into site 6 led to calculated binding free energies matching the experimental ones. Our results provide strong evidence about the allosteric inhibition of FP-2 through binding of small molecules to site 6, thus opening the way toward the discovery of new inhibitors against this enzyme. (AU)

• Processo FAPESP: 16/24587-9 - Identificação in silico de novos inibidores competitivos e alostéricos das falcipaínas 2 e 3
• Beneficiário: Jorge Enrique Hernández González
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 20/10214-1 - Estratégias computacionais e experimentais integradas para a inibição das toxinas exfoliativas de Staphylococcus aureus
• Beneficiário: Jorge Enrique Hernández González
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/19766-1 - Relevo de superfícies de energia de macromoléculas biológicas com aplicações em biotecnologia e em biomedicina
• Beneficiário: Vitor Barbanti Pereira Leite
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/03911-8 - Desenho baseado em estrutura de inibidores alostéricos e competitivos da cruzaína
• Beneficiário: Lilian Hernández Alvarez
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 19/22540-3 - Estudos de relevo de superfícies de energia de macromoléculas biológicas
• Beneficiário: Vitor Barbanti Pereira Leite
• Modalidade de apoio: Auxílio à Pesquisa - Regular