Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Department of Biotechnology and Bioengineering, Izmir Institute of Technology, Izmir, Turkey.
Sci Rep. 2024 Oct 30;14(1):26085. doi: 10.1038/s41598-024-77104-3.
Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.
卵磷脂胆固醇酰基转移酶（LCAT）作为一种关键酶，通过胆固醇逆转运来维持胆固醇的体内平衡，这一过程与动脉粥样硬化的发生密切相关。LCAT 功能受损可导致严重的 LCAT 缺乏症，目前尚无药物治疗方法。针对 LCAT 缺乏症和动脉粥样硬化的 LCAT 为基础的治疗方法，如小分子正变构调节剂（PAMs），具有广阔的前景，尽管它们对动脉粥样硬化的疗效仍具有挑战性。在此，我们利用一种定量的计算指标来预测新型 PAMs 的活性，并通过体外酶促测定来测试它们的效力。正如预测的那样，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂（格列净）、蔗糖和类黄酮可激活 LCAT。这对格列净的作用机制具有重要意义，格列净通常用于治疗 2 型糖尿病，也对 LCAT 的内源性激活具有重要意义。我们的研究结果强调了分子动力学模拟在合理药物设计中的潜力。
