Samizo Shigeyoshi, Kaneko Hiromasa
Department of Applied Chemistry, School of Science and Technology, Meiji University, 1-1-1 Higashi-Mita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan.
ACS Omega. 2023 Jul 18;8(30):27247-27255. doi: 10.1021/acsomega.3c02567. eCollection 2023 Aug 1.
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: = 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.
随着血液中胆固醇水平升高，它会在血管内膜积聚，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在改善血液胆固醇水平方面是有效的。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），这是胆固醇合成中的限速酶。已知他汀类药物通过转运至肝脏发挥作用，在肝脏中它们被有机阴离子转运多肽1B1（OATP1B1）摄取。因此，我们推测一种具有高HMGR抑制活性且对OATP1B1具有高亲和力的化合物将是一种具有更高肝脏选择性和更少副作用的高胆固醇血症新型治疗药物。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，以提出一种具有高抑制活性和高肝脏选择性的高胆固醇血症新型治疗药物的化学结构。构建的HMGR抑制活性和OATP1B1亲和力预测模型对测试数据具有较高的预测准确性：分别为0.772和0.768。然后将新的化学结构输入这些模型中以寻找候选化合物。我们发现了一些化合物，其HMGR抑制活性和OATP1B1亲和力高于最新开发的他汀类药物瑞舒伐他汀，并且发现了一些不具有高HMGR抑制活性他汀类药物共同结构的化合物。
