Structure-activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists.

The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg(1)-Arg(2)-2-Nal(3)-Gly(4)-D-Tyr(5)-), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases. While the structure-activity relationships for Arg(1), Arg(2), and Gly(4) are well established, less is understood about the roles of the aromatic residues 2-Nal(3) and D-Tyr(5). Here we report further structure-activity relationship studies of these two positions, which showed that (i) the distal aromatic ring of the 2-Nal(3) side chain is required in order to maintain high potency and (ii) replacement of D-Tyr(5) with conformationally constrained analogues results in significantly reduced activity.

Rational design of conformationally constrained cyclopentapeptide antagonists for C-x-C chemokine receptor 4 (CXCR4).

In the absence of an experimentally determined binding mode for the cyclopentapeptide CXCR4 antagonists, we have rationally designed conformationally constrained analogues to further probe the small peptide binding pocket of CXCR4. Two different rigidification strategies were employed, both resulting in highly potent ligands (9 and 13). The information provided by this cyclopentapeptide ligand series will be very valuable in the development of novel peptidomimetic CXCR4 antagonists.

Molecular modelling and QSAR analysis of some structurally diverse N-type calcium channel blockers.

A quantitative structure-activity relationship (QSAR) analysis was performed on a data set of 104 molecules showing N-type calcium channel blocking activity. Several types of descriptors, including electrotopological, structural, thermodynamics and ADMET, were used to derive a quantitative relationship between N-type calcium channel blocking activity and structural properties. The genetic algorithm-based genetic function approximation (GFA) method of variable selection was used to generate the 2D-QSAR model.

Comparative molecular field analysis and comparative molecular similarity indices analysis of hydroxyethylamine derivatives as selective human BACE-1 inhibitor.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), on a series of 43 hydroxyethylamine derivatives, acting as potent inhibitors of beta-site amyloid precursor protein (APP) cleavage enzyme (BACE-1). The crystal structure of the BACE-1 enzyme (PDB ID: 2HM1) with one of the most active compound 28 was available, and we assumed it to be the bioactive conformation of the studied series, for 3D-QSAR analysis. Statistically significant 3D-QSAR model was established on a training set of 34 compounds, which were validated by a test set of 9 compounds.