hCES1 and hCES2 mediated activation of epalrestat-antioxidant mutual prodrugs: Unwinding the hydrolytic mechanism using in silico approaches.

Herein, we report four series of mutual prodrugs of epalrestat by combining it with different antioxidants using glycine, beta-alanine, and phenylalanine as a linker and by directly linking them through an ester linkage. The designed prodrugs were subjected to pharmacophore and docking-based virtual screening to determine the susceptibility of these prodrugs to be hydrolyzed by human carboxylesterases (hCES1 and hCES2). Five best prodrugs from each series were further submitted to detailed mechanistic study of hCES1 and hCES2 based hydrolytic activation using quantum mechanics and molecular dynamics approach. Additionally, Verloop'ssterimol parameters (B1-B5, L) were calculated in order to investigate the steric constraint of prodrugs to the catalytic sites of hCES1 and hCES2 enzymes. Our results indicated that, among these prodrugs, EP-D4, EP-E13, EP-F5, and EP-F14 are best substrates for hCES1 while EP-G3 and EP-G15 are potential substrates for hCES2. On the other hand, EP-D19 serves as good substrates for both enzymes. Image 1 • Epalrestat-antioxidant mutual prodrugs were designed. • Homology model was built for hCES2. • Pharmacophore models were generated for both hCES1 and hCES2. • Molecular docking and dynamics simulations were performed. • Quantum mechanical and sterimol parameters were calculated to determine the catalytic efficiency of hCES1 and hCES2. [ABSTRACT FROM AUTHOR]