01780nas a2200217   4500008004100000020001400041245010500055210006900160260001600229300001000245490000700255520110000262100002101362700001801383700001801401700002101419700002201440700002101462700002401483856005501507       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.1 aNiemelä, Akseli1 aGiorgi, Laura1 aNouri, Sirine1 aYurttaş, Betül1 aRauniyar, Khushbu1 aJeltsch, Michael1 aKoivuniemi, Artturi  uhttps://www.nature.com/articles/s41598-024-77104-3