biological exploration of ((substituted-phenyl-1𝐻-pyrazol-4-yl) methylene) aniline derivatives as potential dpp-iv inhibitors: admet screening, molecular docking, and dynamics simulations

Using thorough admet screening and computational analysis, the objective of this work was to assess the potential of some substituted-phenyl-1h-pyrazol-4-yl) methylene) aniline derivatives (st-1 to st-30) as prospective dpp-iv inhibitors for the t2dm treatment. remarkably, all the derivatives exhibited better docking scores (-8.5 to -9.6 kcal/mol) compared to anagliptin (-7.6 kcal/mol) and formed more stable complexes. this suggests that the derivatives exhibit a higher potential to inhibit dpp-iv enzyme activity. among these powerful derivatives, st-24 exhibited the greatest level of activity. st-24 displayed the lowest binding free energy of -9.6 kcal/mol. there was seven hydrogen bonds formed between the amino acids arg358, pro359, ser630 (conventional; halogen; f), tyr666 (halogen; f), glu206 (carbon), and his126 (carbon). it has formed some hydrophobic interactions with phe357 (π-π stacked), tyr666 (a π-π t-shaped), and arg358 (π-alkyl). it has established five electrostatic interactions with ser630 (halogen; f), glu206 (attractive charge), phe357 (π-cation), and arg125 (π-cation). through molecular dynamics (md) simulations, the binding stability of st-24 with the dpp-iv enzyme (pdb id: 3wqh) was investigated. the md simulation clearly showed that the amino acids at the binding site did not undergo significant local conformational changes with compound st-24 (less than 2 å). this confirms the overall stability of the binding pocket throughout the simulation. this work has established that these compounds exhibit sufficient admet profiles and binding affinity with dpp-iv enzyme, indicating their potential for future development for biological assessment.