Enzyme Technology Laboratory, Department of Biotechnology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.
Comput Biol Med. 2012 Feb;42(2):156-63. doi: 10.1016/j.compbiomed.2011.11.003. Epub 2011 Dec 15.
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the conversion of HMG-CoA to mevalonate, a four-electron oxidoreduction that is the rate-limiting step in the synthesis of cholesterol and other isoprenoids. This study was designed to understand the mode of interactions of HMGCR isoform 2 with other statins. Hence, ligands such as Atorvastatin (DB01076), Lovastatin (DB00227), Fluvastatin (DB01095), Simvastatin (DB00641), Pravastatin (DB00175), Rosuvastatin (DB01098) and Cerivastatin (DB00439) were docked with enzymes HMGCR isoform 1 (pdb: 1DQ8) and modeled HMGCR isoform 2 (gi|196049380). Our homology modeling results were further processed to model the structure of human HMGCR isoform 2 and its accuracy was confirmed through RMS Z-scores (1.249). These interactions revealed that binding residues such as Arg515, Asp516, Tyr517 and Asn518 are found to be conserved in HMGCR isoform 2 with various statins. Our studies further concluded that Atorvastatin is most efficient inhibitor against both the isoforms of HMGCR whereas HMGCR isoform 2 shows less effectiveness with statins when compared with HMGCR isoform 1.
酶 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR) 催化 HMG-CoA 转化为甲羟戊酸，这是一个四电子氧化还原反应，是胆固醇和其他异戊二烯合成的限速步骤。本研究旨在了解 HMGCR 同工型 2 与其他他汀类药物相互作用的模式。因此，对阿托伐他汀 (DB01076)、洛伐他汀 (DB00227)、氟伐他汀 (DB01095)、辛伐他汀 (DB00641)、普伐他汀 (DB00175)、罗苏伐他汀 (DB01098) 和西立伐他汀 (DB00439) 等配体与 HMGCR 同工型 1 (pdb: 1DQ8) 和建模 HMGCR 同工型 2 (gi|196049380) 进行对接。我们的同源建模结果进一步处理，以模拟人 HMGCR 同工型 2 的结构，其准确性通过 RMS Z 分数 (1.249) 得到证实。这些相互作用表明，结合残基如 Arg515、Asp516、Tyr517 和 Asn518 在 HMGCR 同工型 2 中与各种他汀类药物被发现是保守的。我们的研究进一步得出结论，阿托伐他汀是针对 HMGCR 两种同工型最有效的抑制剂，而 HMGCR 同工型 2 与 HMGCR 同工型 1 相比，对他汀类药物的效果较低。
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