Cluster significance analysis of the anticholesterolemic action of acyl-CoA cholesterol: acyltransferase inhibitors.
Miguel Angel Ordorica Vargas, María De la Luz Velázquez Monroy, Juan Guillermo Ordorica Vargas, Pedro A Lehmann Feitler · PubMed · 2002
Cluster Significance Analysis. In this method, the average distance between the members of the active set is calculated, and used as a limit (DL) to determine how many of all the possible sets of the same size, that can be formed with all the elements of the sample, have a distance as small as, or smaller than DL (Na). With 65 five compounds in the sample, there are a total of 696 190 656 different sets that can be made taking 7 compounds at a time (Nt). Heart disease is a major health problem worldwide. It has been established that hypercholesterolemia is a risk factor in the onset of these diseases. Several pharmacological strategies have been used to develop plasma cholesterol lowering agents. One of those is the inhibition of acyl-CoA cholesterol: acyltransferase (ACAT, EC 2.3.1.26). ACAT is an endoplasmic reticulum-bound enzyme that catalyses the formation of cholesteryl esters from cholesterol and long chain fatty acids in a wide variety of cells. ACAT plays a major role in cellular cholesterol homeostasis [1]. Cholesteryl esters are stored as cytoplasmic storage droplets or, in lipoprotein secreting cells, can be packaged in the hydrophobic core of lipoproteins for transport. In early atherogenesis, macrophages and smooth muscle cells accumulate large quantities of cholesteryl ester, a process catalyzed by ACAT. The cholesterol is derived from atherogenic lipoproteins present in the arterial intima. Intestinal and hepatic ACAT synthesize the majority of cholesteryl esters transported in lipoproteins with atherogenic potential, namely, chylomicron remnants, VLDL remnants and LDL. Thus, there is considerable interest in the potential for ACAT inhibitors to prevent atherogenesis [2]. If a property or combination of properties, is related to the activity, there will be only a small number of samples with an average distance as small as, or smaller than, the set of active compounds, and the significance, calculated as the ratio Na/Nt, will be small. If the property or properties are not important then the ratio will be large. This number is interpreted as the probability of obtaining the clustering by chance alone [3].