Discovery of novel InhA reductase inhibitors: application of pharmacophore- and shape-based screening approach.

BACKGROUND: InhA is a promising and attractive target in antimycobacterial drug development. InhA is involved in the reduction of long-chain trans-2-enoyl-ACP in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis. Recent studies have demonstrated that InhA is one of the targets for the second line antitubercular drug ethionamide. RESULTS: In the current study, we have generated quantitative pharmacophore models using known InhA inhibitors and validated using a large test set. The validated pharmacophore model was used as a query to screen an in-house database of 400,000 compounds and retrieved 25,000 hits. These hits were further ranked based on its shape and feature similarity with potent InhA inhibitor using rapid overlay of chemical structures (OpenEye™) and subsequent hits were subjected for docking. Based on the pharmacophore, rapid overlay of chemical structures model and docking interactions, 32 compounds with more than eight chemotypes were selected, purchased and assayed for InhA inhibitory activity. Out of the 32 compounds, 28 demonstrated 10-38% inhibition against InhA at 10 µM. CONCLUSION: Further optimization of these analogues is in progress and will update in due course.

3D QSAR CoMFA/CoMSIA and docking studies on azole dione derivatives, as anti-cancer inhibitors.

Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of 103 azole dione derivatives, as selective anti-cancer inhibitors. The atom and shape based root mean square alignment yielded the best predictive CoMFA model q² = 0.923, r² = 0.980, when compared with the CoMSIA model. Docking studies were employed to position the inhibitors into active site of Crystal Structure of Delta (4)-3-ketosteroid 5-beta-reductase (PDB id: 3BUR). Results that indicate steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor substituents play a significant role in design novel, potent and selective anti-cancer activity of the compounds.

3D-QSAR studies on CCR2B receptor antagonists: Insight into the structural requirements of (R)-3-aminopyrrolidine series of molecules based on CoMFA/CoMSIA models.

OBJECTIVE: Monocyte chemo attractant protein-1 (MCP-1) is a member of the CC-chemokine family and it selectively recruits leukocytes from the circulation to the site of inflammation through binding with the chemotactic cytokine receptor 2B (CCR2B). The recruitment and activation of selected populations of leukocytes is a key feature in a variety of inflammatory conditions. Thus MCP-1 receptor antagonist represents an attractive target for drug discovery. To understand the structural requirements that will lead to enhanced inhibitory potencies, we have carried out 3D-QSAR (quantitative structure-activity relationship) studies on (R)-3-aminopyrrolidine series of molecules as CCR2B receptor antagonists. MATERIALS AND METHODS: Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of (R)-3-aminopyrrolidine derivatives as antagonists of CCR2B receptor with Sybyl 6.7v. RESULTS: We have derived statistically significant model from 37 molecules and validated it against an external test set of 13 compounds. The CoMFA model yielded a leave one out r(2) (r(2) (loo)) of 0.847, non-cross-validated r(2) (r(2) (ncv)) of 0.977, F value of 267.930, and bootstrapped r(2) (r(2) (bs)) of 0.988. We have derived the standard error of prediction value of 0.367, standard error of estimate 0.141, and a reliable external predictivity, with a predictive r(2) (r(2) (pred)) of 0.673. While the CoMSIA model yielded an r(2) (loo) of 0.719, r(2) (ncv) of 0.964,F value of 135.666, r(2) (bs) of 0.975, standard error of prediction of 0.512, standard error of estimate of 0.180, and an external predictivity with an r(2) (pred) of 0.611. These validation tests not only revealed the robustness of the models but also demonstrated that for our models r(2) (pred), based on the mean activity of test set compounds can accurately estimate external predictivity. CONCLUSION: The QSAR model gave satisfactory statistical results in terms of q(2) and r(2) values. We analyzed the contour maps obtained, to study the activity trends of the molecules. We have tried to demonstrate structural features of compounds to account for the activity in terms of positively contributing physicochemical properties such as steric, electrostatic, hydrophobic, hydrogen bond donor, and acceptor fields. These contour plots identified several key features, which explain the wide range of activities. The results obtained from models offer important structural insight into designing novel CCR2B antagonists before their synthesis.

Streptomyces hyderabadensis sp. nov., an actinomycete isolated from soil.

A novel actinomycete, designated strain OU-40(T), was isolated from farm soil collected from the Hyderabad region of Andhra Pradesh, southern India. The strain was found to have morphological and chemotaxonomic characteristics typical of species of the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain OU-40(T) belonged to the genus Streptomyces, and was related most closely to Streptomyces pactum NBRC 13433(T) (99.0 % sequence similarity), Streptomyces olivaceus NBRC 12805(T) (99.0 %) and Streptomyces parvulus NBRC 13193(T) (98.8 %). Strain OU-40(T) could be distinguished from the type strains of its closest phylogenetic relatives based on levels of DNA-DNA relatedness and comparison of morphological and phenotypic data. It is therefore concluded that strain OU-40(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces hyderabadensis sp. nov. is proposed. The type strain is OU-40(T) (=CCTCC AA 209024(T) =PCM 2692(T)).

Streptomyces osmaniensis sp. nov., isolated from soil.

A novel actinomycete, designated strain OU-63T, was isolated from garden soil collected on the campus of Osmania University in Hyderabad, southern India. The strain was found to have morphological and chemotaxonomic characteristics typical of the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain belonged to the genus Streptomyces, and was related most closely to Streptomyces chartreusis NBRC 12753T (98.6% similarity). However, the mean level of DNA-DNA relatedness between the two strains was only 25+/-1.73%. Based on DNA-DNA relatedness, morphological and phenotypic data, strain OU-63T could be distinguished from the type strains of phylogenetically related species. It is therefore considered to represent a novel species of the genus Streptomyces, for which the name Streptomyces osmaniensis sp. nov. is proposed. The type strain is OU-63T (=CCTCC AA209025T =PCM 2690T).