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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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de Oliveira, Ivan Pires [1] ; Lescano, Caroline Honaiser [2] ; De Nucci, Gilberto [2, 1]
Total Authors: 3
[1] Univ Sao Paulo, Inst Biomed Sci, Sao Paulo, SP - Brazil
[2] Univ Estadual Campinas, Fac Med Sci, Campinas, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: CHEMICAL BIOLOGY & DRUG DESIGN; v. 93, n. 4, p. 419-429, APR 2019.
Web of Science Citations: 2

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)

FAPESP's process: 10/16947-9 - Correlations between dynamics, structure and function in protein: computer simulations and algorithms
Grantee:Leandro Martinez
Support type: Regular Research Grants
FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
Grantee:Munir Salomao Skaf
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 13/05475-7 - Computational methods in optimization
Grantee:Sandra Augusta Santos
Support type: Research Projects - Thematic Grants