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000639284 1001_ $$0P:(DE-H253)PIP1032135$$aRasheed, Saima$$b0$$eCorresponding author
000639284 245__ $$aDrug repurposing: Identification and X-ray crystallographic analyses of US-FDA approved drugs against carbonic anhydrase-II
000639284 260__ $$aNew York, NY [u.a.]$$bElsevier$$c2025
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000639284 520__ $$aOf all isoforms, human carbonic anhydrase II (PF00194; EC 4.2.1.1), which is mostly found in red cells, kidneys, and the eyes, plays a pivotal role in numerous physiological processes, and its dysregulation has been linked to the wide range of illnesses, such as glaucoma. Finding new inhibitors that target carbonic anhydrase II, therefore has great potential in drug discovery. Using drug repurposing approach, this study focused on the investigation of different drugs as Carbonic anhydrase II inhibitors and their structural studies using X-ray crystallography. For this purpose, 100 different drugs were evaluated for bovine and human carbonic anhydrase II inhibitory activity. Among all, two drugs, i.e. acetohexamide (1) and levosulpiride (54) were found to be active, with IC$_{50}$ = 437.0 ± 0.2 and 1128 ± 0.75 μM, respectively. Mechanistic studies suggested that both drugs are competitive inhibitors of the human carbonic anhydrase II enzyme. The X-ray crystal structure analysis revealed that acetohexamide (1) interacts via terminal acetyl group with the active site residues of the carbonic anhydrase II enzyme, and showed strong hydrogen bonding with Zn, His94, His119, and Asn67. The sulfonamide group of levosulpiride was involved in strong hydrogen bonding with Zn, His94, His119, and Thr199. From in vivo studies, we found that carbonic anhydrase activity was significantly inhibited by the intraperitoneal administration of levosulpiride for up to 5 h. Our findings provide comprehensive insights for the optimization of the pharmacological profile of these drugs, and provide avenues for the exploration of different derivatives of these drugs with enhanced efficacy and fewer adverse effects.
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000639284 7001_ $$0P:(DE-HGF)0$$aHuda, Noo rul$$b1
000639284 7001_ $$0P:(DE-HGF)0$$aWarsi, Zoha$$b2
000639284 7001_ $$0P:(DE-HGF)0$$aTahir, Syeda Sarah$$b3
000639284 7001_ $$0P:(DE-H253)PIP1032133$$aAhmad, Malik Shoaib$$b4
000639284 7001_ $$0P:(DE-HGF)0$$aGul, Sadaf$$b5
000639284 7001_ $$0P:(DE-HGF)0$$aArif, Rida$$b6
000639284 7001_ $$0P:(DE-H253)PIP1089186$$aFalke, Sven$$b7
000639284 773__ $$0PERI:(DE-600)1483284-7$$a10.1016/j.ijbiomac.2025.141057$$gVol. 305, p. 141057 -$$p141057 $$tInternational journal of biological macromolecules$$v305$$x0141-8130$$y2025
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