Clinical Biochemistry Unit, Department of Pathology, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
Dr. Panjwani Center for Molecular Medicine & Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75210, Pakistan.
Comput Biol Chem. 2022 Jun;98:107647. doi: 10.1016/j.compbiolchem.2022.107647. Epub 2022 Feb 25.
Isomerism plays a key role in determining potency, selectivity and type of inhibition exhibited by enzyme inhibitors. We present 20 new benzylidene-hydrazinyl-thiazole inhibitors of α-glucosidase featuring positional isomerism of the methyl group at 3 and 4 positions of their piperidine ring. This structural property helped understand their potency and selectivity to the enzyme yielding new clues to α-glucosidase inhibition. The isomerism was pivotal to improving or deteriorating enzyme binding and potency of inhibition shown by the target compounds. Data from enzyme kinetics experiments were in agreement with docking and molecular dynamics simulations revealing a direct influence of isomerism on enzyme-inhibitor molecular interactions. Generally, the 4-methyl derivatives showed more selectivity toward the enzyme since they established more and stronger molecular contacts with the enzyme than their 3-methyl counterparts. However, the isomerism did not significantly affect the type of inhibition since majority of the compounds exhibited noncompetitive enzyme inhibition except for one. Our work provides essential and interesting clues to understanding α-glucosidase inhibition by thiazole isomers that would help explore new avenues to designing and developing better α-glucosidase inhibitors as antidiabetic drugs.
异构现象在决定酶抑制剂的效力、选择性和抑制类型方面起着关键作用。我们提出了 20 种新的苯亚甲基-腙-噻唑α-葡萄糖苷酶抑制剂，其哌啶环的 3 位和 4 位的甲基具有位置异构性。这种结构特性有助于了解它们对酶的效力和选择性，为α-葡萄糖苷酶抑制提供了新的线索。异构现象对于改善或恶化目标化合物的酶结合和抑制效力至关重要。来自酶动力学实验的数据与对接和分子动力学模拟结果一致，表明异构现象对酶-抑制剂分子相互作用有直接影响。一般来说，4-甲基衍生物对酶的选择性更高，因为它们与酶建立了更多和更强的分子相互作用，而它们的 3-甲基对应物则没有。然而，异构现象并没有显著影响抑制类型，因为除了一种化合物外，大多数化合物都表现出非竞争性的酶抑制。我们的工作为理解噻唑异构体对α-葡萄糖苷酶的抑制提供了重要而有趣的线索，这将有助于探索设计和开发更好的α-葡萄糖苷酶抑制剂作为抗糖尿病药物的新途径。
