Q817G mutation in phosphodiesterase type 5: Conformational analysis and dissociation profile of the inhibitor Tadalafil

Autor(es)

de Oliveira, Ivan Pires ^[1] ; Lescano, Caroline Honaiser ^[2] ; De Nucci, Gilberto ^{[2, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo, SP - Brazil

^[2] Univ Estadual Campinas, Fac Med Sci, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CHEMICAL BIOLOGY & DRUG DESIGN; v. 93, n. 4, p. 419-429, APR 2019.
• Citações Web of Science: 2

Resumo

Phosphodiesterase type 5 (PDE-5) is an important enzyme involved in the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). The inhibition of this protein leads to the accumulation of cGMP in cells with various biological and therapeutic effects. Several PDE-5 inhibitors exist, with Tadalafil being one of the most commonly studied and used in clinical therapy. In this study, we applied Molecular Dynamics simulations coupled to the ABF (Adaptive Biasing Force) method to study the effect of the mutation on the Gln817 residue (Q817G). The results of the free energy profiles made clear that the affinity of the inhibitor for PDE-5 is dependent on the amino acid residue Gln817. The hydrogen bond made between the side chain of glutamine and the indole ring of Tadalafil results in the stabilization of the ligand in the catalytic site. Despite the prominent role of this interaction, it is important to highlight the contribution of other residues of the catalytic domain for the stabilization of the compound, due to the set of polar, hydrophobic and electrostatic interactions performed by specific amino acid residues. (AU)

• Processo FAPESP: 13/08293-7 - CECC - Centro de Engenharia e Ciências Computacionais
• Beneficiário: Munir Salomao Skaf
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 13/05475-7 - Métodos computacionais de otimização
• Beneficiário: Sandra Augusta Santos
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/16947-9 - Estrutura, dinâmica e função em proteínas: simulação computacional e desenvolvimento de algoritmos
• Beneficiário: Leandro Martinez
• Modalidade de apoio: Auxílio à Pesquisa - Regular