Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening.

Seven novel binders, binding in the active site of Plasmodium falciparum spermidine synthase, were identified by structure-based virtual screening. The binding of these compounds was experimentally verified by NMR techniques. Spermidine synthase, an enzyme involved in the polyamine pathway, has been suggested as a target for treating malaria.

Are automated molecular dynamics simulations and binding free energy calculations realistic tools in lead optimization? An evaluation of the linear interaction energy (LIE) method.

An extensive evaluation of the linear interaction energy (LIE) method for the prediction of binding affinity of docked compounds has been performed, with an emphasis on its applicability in lead optimization. An automated setup is presented, which allows for the use of the method in an industrial setting. Calculations are performed for four realistic examples, retinoic acid receptor gamma, matrix metalloprotease 3, estrogen receptor alpha, and dihydrofolate reductase, focusing on different aspects of the procedure.

Ligand bias of scoring functions in structure-based virtual screening.

A total of 945 known actives and roughly 10 000 decoy compounds were docked to eight different targets, and the resulting poses were scored using 10 different scoring functions. Three different score postprocessing methods were evaluated with respect to improvement of the enrichment in virtual screening. The three procedures were (i) multiple active site correction (MASC) as has been proposed by Vigers and Rizzi, (ii) a variation of MASC where corrections terms are predicted from simple molecular descriptors through PLS, PLS MASC, and (iii) size normalization.

Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site.

Ribose-5-phosphate isomerases (EC 5.3.1.

Improving structure-based virtual screening by multivariate analysis of scoring data.

Three different multivariate statistical methods, PLS discriminant analysis, rule-based methods, and Bayesian classification, have been applied to multidimensional scoring data from four different target proteins: estrogen receptor alpha (ERalpha), matrix metalloprotease 3 (MMP3), factor Xa (fXa), and acetylcholine esterase (AChE). The purpose was to build classifiers able to discriminate between active and inactive compounds, given a structure-based virtual screen. Seven different scoring functions were used to generate the scoring matrices.

Crystal structure of the heterodimeric complex of LXRalpha and RXRbeta ligand-binding domains in a fully agonistic conformation.

The nuclear receptor heterodimers of liver X receptor (LXR) and retinoid X receptor (RXR) are key transcriptional regulators of genes involved in lipid homeostasis and inflammation. We report the crystal structure of the ligand-binding domains (LBDs) of LXRalpha and RXRbeta complexed to the synthetic LXR agonist T-0901317 and the RXR agonist methoprene acid (Protein Data Base entry 1UHL). Both LBDs are in agonist conformation with GRIP-1 peptides bound at the coactivator binding sites.

Genome-based identification and analysis of collagen-related structural motifs in bacterial and viral proteins.

Collagens are extended trimeric proteins composed of the repetitive sequence glycine-X-Y. A collagen-related structural motif (CSM) containing glycine-X-Y repeats is also found in numerous proteins often referred to as collagen-like proteins. Little is known about CSMs in bacteria and viruses, but the occurrence of such motifs has recently been demonstrated.

A triple mutant of the Drosophila ERR confers ligand-induced suppression of activity.

The steroid hormone (NR3) subfamily of nuclear receptors was until recently believed to be restricted to deuterostomes. However, a novel nuclear receptor belonging to the NR3 subfamily was recently identified in the Drosophila melanogaster genome, indicating the existence of an ancestor before the evolutionary split of deuterostomes and protostomes. This receptor, termed the Drosophila estrogen-related receptor (dERR), most closely resembles the human and mouse estrogen-related receptors (ERRs) in both the DNA binding domain (DBD) (approximately 85% identical) and the ligand binding domain (LBD) (approximately 35% identical).