Virtual screening for cholesterol absorption inhibitors.
BACKGROUND
Cholesterol, derived from two different sources of endogenous synthesis and diet, is essential for the growth and maintenance of mammalian cells. However, elevated level of serum cholesterol is among the associated risk factors for the coronary heart disease. Statins can reduce endogenous sterol synthesis by inhibiting HMG-CoA reductase, whereas cholesterol absorption inhibitors, such as ezetimibe, can block cholesterol uptake from dietary sources by blocking Niemann- Pick C1-like 1 (NPC1L1).


OBJECTIVE
The present review focuses on the main research progress of cholesterol absorption inhibitors, the structure of NPC1L1 and discovery of novel chemical entities by virtual screening.


CONCLUSIONS
Studies on the structure-activity relationship reveal that azetidinone is important to maintain activity in azetidinone derivatives and the novel heterocyclic compounds with replacement of β-lactam scaffold by oxazolidinone also show similar activity as ezetimibe. Moreover, virtual screening is a computer-aided molecular design tool to propose novel cholesterol absorption inhibitors.
Lidan
L
Sun
Hai
H
Qian
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. qianhai24@163.com.
Wenlong
W
Huang
D000818:Animals; D000924:Anticholesteremic Agents / Q000737:chemistry* / Q000494:pharmacology; D001384:Azetidines / Q000737:chemistry* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D003327:Coronary Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000069438:Ezetimibe; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
C116379:2-azetidinone; D000924:Anticholesteremic Agents; D001384:Azetidines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C410800:NPC1L1 protein, human; D002784:Cholesterol; D000069438:Ezetimibe