HMG-CoA 还原酶抑制活性的预测模型和新型 HMG-CoA 还原酶抑制剂的设计,ACS Omega

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HMG-CoA 还原酶抑制活性的预测模型和新型 HMG-CoA 还原酶抑制剂的设计
ACS Omega ( IF 3.7 ) Pub Date : 2023-07-18 , DOI: 10.1021/acsomega.3c02567
Shigeyoshi Samizo ₁ , Hiromasa Kaneko ₁

Affiliation

随着血液中胆固醇的增加，它会积聚在血管内膜中，增加动脉粥样硬化和冠状动脉疾病的风险。抑制胆固醇合成所必需的酶的药物可有效改善血液胆固醇水平。他汀类药物用于治疗高胆固醇血症，因为它们抑制 3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶 (HMGR)，胆固醇合成中的限速酶。众所周知，他汀类药物通过转运至肝脏来发挥作用，在肝脏中它们被有机阴离子转运多肽 1B1 (OATP1B1) 吸收。因此，我们假设具有高 HMGR 抑制活性和对 OATP1B1 高亲和力的化合物将是一种优异的高胆固醇血症新治疗剂，具有增加的肝脏选择性和更少的副作用。在本研究中，我们开发了两种预测 HMGR 抑制活性和 OATP1B1 亲和力的模型，提出了一种具有高抑制活性和高肝脏选择性的新型高胆固醇血症治疗剂的化学结构。构建了HMGR抑制活性和OATP1B1亲和力预测模型，对测试数据预测精度较高：r ²分别= 0.772和0.768。然后将新的化学结构输入到这些模型中以搜索候选化合物。我们发现了比最新开发的他汀类药物瑞舒伐他汀具有更高 HMGR 抑制活性和 OATP1B1 亲和力的化合物，以及不具有高 HMGR 抑制活性他汀类药物的共同结构的化合物。

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Predictive Modeling of HMG-CoA Reductase Inhibitory Activity and Design of New HMG-CoA Reductase Inhibitors

As blood cholesterol increases, it accumulates in the intima of blood vessels, elevating the risk of atherosclerosis and coronary artery disease. Drugs that inhibit enzymes essential for cholesterol synthesis are effective in improving blood cholesterol levels. Statins are used to treat hypercholesterolemia as they inhibit 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR), the rate-limiting enzyme in cholesterol synthesis. Statins are known to exert their effects by translocating to the liver, where they are taken up by the organic anion transporting polypeptide 1B1 (OATP1B1). Therefore, we hypothesized that a compound with high HMGR inhibitory activity and high affinity for OATP1B1 would be an excellent new therapeutic agent for hypercholesterolemia with increased liver selectivity and fewer side effects. In this study, we developed two models for predicting HMGR inhibitory activity and OATP1B1 affinity to propose the chemical structure of a new therapeutic agent for hypercholesterolemia with both high inhibitory activity and high liver selectivity. HMGR inhibitory activity and OATP1B1 affinity prediction models were constructed with high prediction accuracy for the test data: r² = 0.772 and 0.768, respectively. New chemical structures were then input into these models to search for candidate compounds. We found compounds with higher HMGR inhibitory activity and OATP1B1 affinity than rosuvastatin, the most recently developed statin drug, and compounds that did not have a common structure of statins with high HMGR inhibitory activity.

更新日期：2023-07-18

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