Biological Exploration of ((Substituted-Phenyl-1H-Pyrazol-4-yl) Methylene) Aniline Derivatives as Potential DPP-IV Inhibitors: ADMET Screening, Molecular Docking, and Dynamics Simulations
نویسندگان
1 Department of Pharmaceutics, Malla Reddy Institute of Pharmaceutical Sciences, Hyderabad, Telangana, India
2 Department of Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research (Deemed to be University), Guntur-Tenali Rd, Vadlamudi, Andhra Pradesh 522213, India
3 Institute of Pharmaceutical Research, GLA University Mathura, Uttar Pradesh, India
4 Department of Pharmacy, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai. Tamil Nadu, India
5 Department of Pharmaceutics, Vels Institute of Science, Technology and Advanced Studies (VISTAS), PV Vaithiyalingam Rd, Velan Nagar, Krishna Puram, Pallavaram, Chennai, Tamil Nadu, India
6 Senior Research Scientist, Analytical Research and Development, Amneal Pharmaceuticals, Piscataway, New Jersey, USA
7 Department of Pharmaceutical Sciences, Vignan's Foundation for Science, Technology & Research (Deemed to be University), Guntur-Tenali Rd, Vadlamudi, Andhra Pradesh 522213, India
8 Department of Pharmaceutical Analysis, MB School of Pharmaceutical Sciences, Mohan Babu University (Erstwhile Sree Vidyaniketan College of Pharmacy) Tirupati, India
9 Department of Pharmaceutical Chemistry, Mutah University, 61710 Al Karak, Jordan
10 Department of Pharmaceutical Chemistry, Mutah University, 61710 Al Karak, Jordan
11 Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
doi
10.48309/chemm.2025.481887.1834چکیده
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.
