A feature based pharmacophore for Candida albicans MyristoylCoA: protein N-myristoyltransferase inhibitors

A three-dimensional pharmacophore model has been generated for Candida albi cans MyristoylCoA: protein N-myristoyl-transferase (NMT) inhibitors, using the software program CATALYST. The in vitro NMT inhibitory activity of a se ries of peptidic inhibitors was used for pharmacophore generation. The effe ct of altering the control parameters and feature selection was studied to arrive at the pharmacophore model. The selection of the best hypothesis mod el was based on the total cost, predictive ability, difference in the cost from the null hypothesis and alignment of the training set compounds on to the hypothesis. The pharmacophore model selected has four features; one hyd rophobic, two hydrogen bond acceptor and one positive ionisable function. G roups identified as necessary by scanning alanine mutagenesis studies of th e peptidic substrate of C. albicans NMT, have been identified as pharmacoph ore features. Comparison of the ligand binding with the enzyme in the cryst al structure of NMT and that proposed by the phamacophore is consistent. Th e pharmacophore thus generated can be used as a template for designing non- peptidic inhibitors of NMT. (C) 2001 Editions scientifiques et medicales El sevier SAS.