Scior Thomas, Abdallah Hassan H, Mustafa Siti Fatimah Zaharah, Guevara-García José Antonio, Rehder Dieter
Departamento de Farmacia, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla. 72000 Puebla, Pue., Mexico.
Chemistry Department, College of Education, Salahaddin University Erbil, 44001 Erbil, Iraq.
Inorganica Chim Acta. 2021 May 1;519:120287. doi: 10.1016/j.ica.2021.120287. Epub 2021 Feb 11.
techniques helped explore the binding capacities of the SARS-CoV-2 main protease (M) for a series of metalloorganic compounds. Along with small size vanadium complexes a vanadium-containing derivative of the peptide-like inhibitor (N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-N1-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl] methyl }but-2-enyl)-l-leucinamide) was designed from the crystal structure with PDB entry code 6LU7. On theoretical grounds our consensus docking studies evaluated the binding affinities at the hitherto known binding site of Chymotrypsin-like protease (3CLpro) of SARS-CoV-2 for existing and designed vanadium complexes. This main virus protease (M) has a Cys-His dyad at the catalytic site that is characteristic of metal-dependent or metal-inhibited hydrolases. M was compared to the human protein-tyrosine phosphatase 1B (hPTP1B) with a comparable catalytic dyad. HPTP1B is a key regulator at an early stage in the signalling cascade of the insulin hormone for glucose uptake into cells. The vanadium-ligand binding site of hPTP1B is located in a larger groove on the surface of M. Vanadium constitutes a well-known phosphate analogue. Hence, its study offers possibilities to design promising vanadium-containing binders to SARS-CoV-2. Given the favourable physicochemical properties of vanadium nuclei, such organic vanadium complexes could become drugs not only for pharmacotherapy but also diagnostic tools for early infection detection in patients. This work presents the design of a potential lead vanadium compound. It was tested along with 20 other vanadium-containing complexes from the literature in a virtual screening test by docking to inhibit M of SARS-CoV-2.
技术有助于探索严重急性呼吸综合征冠状病毒2（SARS-CoV-2）主要蛋白酶（Mpro）对一系列金属有机化合物的结合能力。除了小尺寸钒配合物外，还根据蛋白质数据银行（PDB）登录号为6LU7的晶体结构设计了一种肽样抑制剂（N-[(5-甲基异恶唑-3-基)羰基]丙氨酰-L-缬氨酰-N1-((1R,2Z)-4-(苄氧基)-4-氧代-1-{[(3R)-2-氧代吡咯烷-3-基]甲基}丁-2-烯基)-L-亮氨酰胺）的含钒衍生物。基于理论依据，我们的共识对接研究评估了SARS-CoV-2类胰凝乳蛋白酶（3CLpro）已知结合位点对现有和设计的钒配合物的结合亲和力。这种主要病毒蛋白酶（Mpro）在催化位点有一个半胱氨酸-组氨酸二元组，这是金属依赖性或金属抑制水解酶的特征。将Mpro与具有类似催化二元组的人蛋白酪氨酸磷酸酶1B（hPTP1B）进行了比较。HPTP1B是胰岛素激素信号级联早期细胞摄取葡萄糖的关键调节因子。hPTP1B的钒-配体结合位点位于Mpro表面的一个较大凹槽中。钒是一种著名的磷酸盐类似物。因此，对其研究为设计有前景的SARS-CoV-2含钒结合剂提供了可能性。鉴于钒核有利的物理化学性质，这种有机钒配合物不仅可以成为药物治疗的药物，还可以成为患者早期感染检测的诊断工具。这项工作展示了一种潜在先导钒化合物的设计。通过对接抑制SARS-CoV-2的Mpro，在虚拟筛选试验中对其与文献中的其他20种含钒配合物进行了测试。
