01551nas a2200133   4500008004100000020001400041245010500055210006900160260001600229300001000245490000700255520110000262856005501362       2024                        eng d  a2045-232200aGliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase0 aGliflozins sucrose and flavonoids are allosteric activators of l  c2024/10/30/  a260850 v143 aAbstract            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.  uhttps://www.nature.com/articles/s41598-024-77104-3