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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: Journal of Computer-Aided Molecular Design; v. 35, n. 10, p. 1067-1079, OCT 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 16/24587-9 - In silico identification of novel competitive and alosteric inhibitors of falcipains 2 and 3
• Grantee: Jorge Enrique Hernández González
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 20/10214-1 - Integrated computational and experimental strategies for the inhibition of exfoliative toxins from Staphylococcus aureus
• Grantee: Jorge Enrique Hernández González
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/19766-1 - Biological macromolecules energy landscapes with applications in biotechnology and in biomedicine
• Grantee: Vitor Barbanti Pereira Leite
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/03911-8 - Structure-based design of competitive and allosteric inhibitors of cruzain
• Grantee: Lilian Hernández Alvarez
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/22540-3 - Studies of energy landscapes of biological macromolecules
• Grantee: Vitor Barbanti Pereira Leite
• Support Opportunities: Regular Research Grants