In silico Screening, Synthesis, and in vitro Enzyme Assay of Some 1,2,3-Oxadiazole-linked Tetrahydropyrimidine-5-carboxylate Derivatives as DPP-IV Inhibitors for Treatment of T2DM
نویسندگان
1 Department of Pharmaceutical Sciences, MITWPU School of Health Sciences and Technology, MIT-World Peace University, Pune, Maharashtra, India
2 Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
3 Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah 11172, United Arab Emirates
4 Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
5 Department of Pharmaceutical Sciences, MITWPU School of Health Sciences and Technology, MIT-World Peace University, Pune, Maharashtra, India
6 Department of Data Science, School of Computing and Informatics, University of North Carolina at Charlotte, USA
7 School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Jadcherla-509301, Hyderabad, India
8 School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Jadcherla-509301, Hyderabad, India
doi
10.48309/chemm.2024.479997.1830چکیده
Some ethyl 2-((1,2,3-oxadiazol-4-yl)thio)-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives (M1 to M20) were designed and developed as potential DPP-IV inhibitors. All the designed derivatives were subjected for binding affinity studies. Fortunately, 18 molecules displayed better binding affinity than native ligand (NL) present in the crystal structure of enzyme (PDB ID: 6B1E). From interactions of NL, it was observed that Glu206 and Arg358 are important amino acid residues to get good binding orientation. Fortunately, almost all the molecules developed at least one kind of interactions with either of these amino acids. Out of these, M17 was considered as most potent as it has developed 5 conventional-hydrogen bonds. To evaluate the stability of Compound M17 in complex with the DPP-IV enzyme, a 100 ns all-atom molecular dynamics (MD) simulation was conducted. The combination of hydrogen bonding, hydrophobic, ionic, and water-mediated interactions highlights the robust nature of the binding between Compound M17 and enzyme, ensuring the stability and efficacy of the complex throughout the simulation. From in silico screening, we have selected M3, M5, M12, M16, M17, and M18 for the synthesis. The synthesized compounds tested at 250 µM and all the compounds exhibited more than 90% of inhibition in in vitro enzyme assay. Compound M18 displayed 93.3±0.58% of inhibition and 13.14±0.49 µM of IC50 value which was highest amongst the synthesized compounds. It was concluded that, the synthesized compounds displayed optimum DPP-IV inhibitory activity, therefore these can be treated as lead nucleus for further development.
