THE INFLUENCE OF DIFFERENT PHENYL MOIETY SUBSTITUTIONS OF SILDENAFIL DERIVATIVES ON THEIR POTENTIAL INTERACTION TOWARD PHOSPHODIESTERASE TYPE-5

Abstract

Sildenafil has FDA approval as the first agent for erectile dysfunction oral therapy. It works by inhibiting the phosphodiesterase type 5 enzyme and preventing the breakdown of cyclic guanosine monophosphate. Therefore, this study aims to modify the structure of sildenafil to obtain a safer derivative with better phosphodiesterase type-5 inhibition activity. An interaction assessment using molecular docking and dynamic simulation (in silico) was carried out to evaluate the interaction affinity of the derivatives with the phenyl moiety, which has different substituents for PDE5. The results showed that the removal of 4-methylpiperazine-sulfonyl and methoxy from the moiety as well as the addition of propyl ether in the para position led to significant changes in pharmacokinetic properties and affinity toward PDE5. This substituent enables two hydrogen interactions between the Gln817 amino acid residue and the pyrazolopyrimidine ring with a binding energy of -115.65 kJ/mol. Through the reduction of competitive interference for H-bonding with water, these interactions indicate the presence of a higher affinity protein-ligand association. Furthermore, the root-mean-square deviation profile of this sildenafil derivative-PDE5 complex was significantly lower compared to the other five ligand-enzyme complexes, and this indicates a stable conformation.