In Silico Mapping of Essential Residues in the Catalytic Domain of PDE5 Responsible for Stabilization of Its Commercial Inhibitors

Author(s)

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

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Estadual Campinas, Sch Med Sci, Dept Pharmacol, BR-13083887 Campinas, SP - Brazil

• Document type: Journal article
• Source: SCIENTIA PHARMACEUTICA; v. 87, n. 4 DEC 2019.
• Web of Science Citations: 0

Abstract

Phosphodiesterase type 5 (PDE5) is an important enzyme associated with the hydrolysis of cyclic guanosine monophosphate (cGMP) to guanosine monophosphate (GMP). Due to the relevant role of second messenger cGMP as a mediator in many physiological processes, efforts have been converged to find a safe pharmacological approach, seeking a specific, selective and potent inhibitor of the PDE5 enzyme. There are five commercial drugs with potential for clinical use: tadalafil, sildenafil, avanafil, udenafil and vardenafil. Here, we applied molecular modeling to obtain different profiles of protein-ligand interactions by adopting distinct PDE5 structures, specifically PDBid:1XOZ and two extracted from molecular dynamics (MD) simulations. The results generated by molecular docking showed several possibilities for inhibitor interactions with the catalytic pocket. Tadalafil, sildenafil and vardenafil were clearly stabilized by Gln817 via a well-oriented hydrogen bond. Another set of different interactions, such as polar, hydrophobic, pi-stacking, metal-ligand and electrostatic, were responsible for accommodating avanafil and udenafil. All of the ligands are discussed in detail with consideration of the distinct protein structures, and a profile of the probability of residue-ligand contact is suggested, with the most frequently observed being: Tyr612, His613, Ser661, Thr723, Asp724, Asp764, Leu765, Val782 and Phe786. The molecular interactions displayed herein confirm findings achieved by previous authors and also present new contacts. In addition, the discussion can help researchers obtain a molecular basis for planning new selective PDE5 inhibitors, as well as explain an inhibitor's experimental assays by considering the specific interactions occurring at the catalytic site. (AU)

• FAPESP's process: 13/22360-9 - Computational Study of the mechanism of conversion of ATP to cyclic-AMP catalyzed by the Edema Factor of Anthrax
• Grantee: Gabriel Ernesto Jara
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 10/16947-9 - Correlations between dynamics, structure and function in protein: computer simulations and algorithms
• Grantee: Leandro Martinez
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
• Grantee: Munir Salomao Skaf
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/05475-7 - Computational methods in optimization
• Grantee: Sandra Augusta Santos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/02201-4 - Study of the inhibition of the accumulation of cyclic nucleotide by pyridopyrimidine derivatives using molecular dynamics simulations
• Grantee: Ivan Pires de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/26687-3 - Pharmacological characterization of glyphlozins in isolated human platelets: in vitro, in vivo evaluation and molecular modeling
• Grantee: Caroline Honaiser Lescano
• Support Opportunities: Scholarships in Brazil - Post-Doctoral