𝐼𝑛 𝑠𝑖𝑙𝑖𝑐𝑜 Screening, Synthesis, and 𝑖𝑛 𝑣𝑖𝑡𝑟𝑜 Enzyme Assay of Some ۱,۲,۳-Oxadiazole-linked Tetrahydropyrimidine-۵-carboxylate Derivatives as DPP-IV Inhibitors for Treatment of T۲DM

Some ethyl ۲-((۱,۲,۳-oxadiazol-۴-yl)thio)-۶-methyl-۱,۲,۳,۴-tetrahydropyrimidine-۵-carboxylate derivatives (M۱ to M۲۰) were designed and developed as potential DPP-IV inhibitors. All the designed derivatives were subjected for binding affinity studies. Fortunately, ۱۸ molecules displayed better binding affinity than native ligand (NL) present in the crystal structure of enzyme (PDB ID: ۶B۱E). From interactions of NL, it was observed that Glu۲۰۶ and Arg۳۵۸ 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, M۱۷ was considered as most potent as it has developed ۵ conventional-hydrogen bonds. To evaluate the stability of Compound M۱۷ in complex with the DPP-IV enzyme, a ۱۰۰ 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 M۱۷ and enzyme, ensuring the stability and efficacy of the complex throughout the simulation. From in silico screening, we have selected M۳, M۵, M۱۲, M۱۶, M۱۷, and M۱۸ for the synthesis. The synthesized compounds tested at ۲۵۰ µM and all the compounds exhibited more than ۹۰% of inhibition in in vitro enzyme assay. Compound M۱۸ displayed ۹۳.۳±۰.۵۸% of inhibition and ۱۳.۱۴±۰.۴۹ µM of IC۵۰ 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.

کلیدواژه ها:

Computational screening ، Pyrimidine ، oxadiazole ، DPP-IV inhibitors ، ADMET