Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

Present study describes the ligand-based molecular modeling along with virtual screening (VS) approach for generation of new tumor necrosis factor-α converting enzyme (TACE) inhibitors. In ligand-based molecular modeling, two statistically reliable HipHop pharmacophore models Hip1 and counter pharmacophore (CP1) were generated using training set of 3 and 2 molecules, respectively. CP1 was generated using inhibitors of MMP-1 (matrix metalloproteinase-1), an important enzyme involved in musculoskeletal degradation. VS was performed with model Hip1 in in-house database of 1.2 million molecules. In addition, the retrieved molecules were screened with CP1. The combination of both models helped for generating new improved TACE inhibitor molecules.     

Development and characterization of lectin-functionalized vesicular constructs bearing amphotericin B for bio-film targeting

The long-term goal of this work will be to develop a topical formulation for oropharyngeal candidosis. Liposomes were prepared by the vesicle extrusion technique from mixtures of dipalmitoylphosphatidylcholine, cholesterol, and stearylamine incorporating a reactive phospholipid, the m-maleimidobenzoyl-N-hydroxysuccinimide ester derivative of dipalmitoylphosphatidylethanolamine, which was conjugated with the N-succinimidyl-S-acetylthioacetate derivatives of succinyl concanavalin A. Morphology of liposomes was studied by transmission electron microscopy and bio-film architecture using fluorescence microscopy. Lectinized vesicles were put into contact with bovine submaxillary mucin, to determine the in vitro activity and specificity. Targeting study was performed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The liposomes were found to have a diameter in the range of 360–450 and 390–510 nm for uncoated and coated formulations, respectively. The MTT assay showed a strong association of lectin-bearing liposomes with candidal bio-film. The results suggest that surface-modified liposomes can effectively target candidal bio-film in vitro.     

3D-QSAR analysis of anilinoquinoline inhibitors of colony stimulating factor-1 kinase (cFMS): implementation of field-based molecular alignment

Colony-stimulating factor-1 receptor (cFMS) serves as a binding site for colony-stimulating factor-1 and is primarily involved in the growth and differentiation of monocytes and macrophages. This crucial function of cFMS links it to various immune system-related disease conditions, such as rheumatoid arthritis, cancer, and immune nephritis. Hence, the potent inhibitors of cFMS may serve novel therapeutic benefits for the treatment of mentioned disease conditions. In the present study, a set of 46 anilinoquinoline derivatives was utilized to perform atom-based 3D-QSAR analysis. The best 3D-QSAR model was selected on the basis of the highest value of Q _test ² , i.e., 0.535. The selected model also displayed high values of R _train ² (0.974), Pearson-r (0.826), and the lowest value of SD (0.099). The contour plots generated for different properties helped to understand biological activity variation pattern with structural changes in molecule at appropriate sites. Therefore, the selected 3D-QSAR model and information revealed from it would provide beneficial guidance for the designing of new potent cFMS inhibitors that can further be explored as novel therapeutic agents for various immune system-related disease conditions.     

Three-dimensional quantitative structure-activity relationship modeling of gamma-secretase inhibitors using molecular field analysis

Three-dimensional quantitative structure-activity relationship analysis of a set of 79 analogs of gamma-secretase inhibitors was performed by molecular field analysis with genetic partial least squares method to investigate the substitutional requirements to derive a predictive model and for the favorable receptor-drug interaction that may be used for the designing of a novel gamma-secretase inhibitors. The developed molecular field analysis model has a good fit, with r2 value of 0.952 and cross-validated coefficient, r2(cv), value of 0.931. Predictive ability of the developed model was further assessed using test set of 19 compounds and r2(pred) was found to be 0.665.     

Pharmacophore and docking-based hierarchical virtual screening for the designing of aldose reductase inhibitors: synthesis and biological evaluation

A set of 54 studied flavonoid inhibitors of aldose reductase (ALR2) enzyme has been utilized for pharmacophore modeling and 3D-QSAR analysis using “PHASE” program of Schrödinger software. The generated pharmacophore model (AADRR.1109) was challenged to screen “PHASE” database to identify new ALR2 inhibitors. The retrieved hits were employed for docking analysis and pharmacokinetic parameter calculation to obtain orally active molecules. To predict the activity of final retrieved hits, 3D-QSAR model was developed, and the best model was selected on the basis of various statistical parameters (R _train ² 0.719; Q _test ² 0.647 and SD 0.663). Totally five screened molecules which showed better enhanced predicted activity were synthesized and evaluated for in vitro ALR2 inhibitory activity. All tested molecules showed ALR2 inhibitory activity (IC₅₀) below 40 µM. Additionally, the free radical scavenging potential of synthesized molecules was also determined which played a useful role to control the progression of diabetic complications. All molecules showed good antioxidant potential, thus the designed molecules, in future, could be explored to ameliorate the development of diabetic complications.     

QSAR analysis of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives as selective COX-2 inhibitors

Quantitative structure-activity relationship (QSAR) analysis was performed on a series of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindole for their cyclooxygenase-2 (COX-2) inhibition. QSAR investigations were based on Hansch's extra thermodynamic multi-parameter approach and receptor surface analysis (RSA). QSAR investigations reveal that steric and electrostatic interactions are primarily responsible for COX-2 enzyme-ligand interaction. QSAR model derived from Hansch analysis demonstrated that COX-2 inhibitory activity is correlated with sum of atomic polarizability (Apol), number of hydrogen-bond donor groups (HBD), energy of the highest occupied molecular orbital (HOMO), desolvation free energy for water (F(H(2)O)) and fraction of areas of molecular shadow in the XY and ZX planes over area of enclosing rectangle (Sxyf and Sxzf) with r ranges 0.870-0.904. The best model was obtained from RSA model having r = 0.940 with good predictive ability (predicted compounds in training set and test set within +/- 1.0 unit of pIC(50)) and can be used in designing better selective COX-2 inhibitors among the congeners in future.     

Three-dimensional quantitative structure activity relationship analysis of anilinoquinazolines for c-Src kinase inhibition

Three-dimensional quantitative structure activity relationship (3D-QSAR) models was developed using molecular field analysis (MFA) for 36 anilinoquinazoline derivatives, inhibiting c-Src kinase. The QSAR model was developed using 29 compounds and its predictive ability was assessed using a test set of seven compounds. The predictive 3D-QSAR model has conventional r ² values of 0.961 while the cross-validated coefficient q ² and bootstrap correlation coefficient r _BS² values of 0.910 and 0.957, respectively. The developed model provides a powerful tool to design potent c-Src inhibitors as novel antitumor agents. Six new inhibitors were designed and their pIC₅₀ were predicted.     

3D-QSAR analysis of benzimidazole inhibitors of interleukin-2 inducible T cell kinase (ITK) considering receptor flexibility and water importance for molecular alignment

Interleukin-2 inducible T cell kinase (ITK) plays an essential role in T cell development, differentiation, and production of Th 2 pro-inflammatory cytokines, such as IL-2, IL-4, IL-5, IL-10, IL-13, and IL-17. Since this kinase is an important contributor in Th 2 cell-mediated autoimmune and allergic disease conditions, e.g. psoriasis, atopic dermatitis, and allergic asthma, the potent inhibitors of ITK may serve as potential therapeutic agents for the treatment of these disease conditions. Thus, a set of 176 benzimidazole ITK inhibitors was employed to perform 3D-QSAR analysis considering the importance of water molecules for docking-based molecular alignment. The best 3D-QSAR model was selected on the basis of the highest value of Q ² _test (0.609). The selected model also displayed the highest values of R ² _train (0.973), F (536.2), and the lowest SD (0.163). The contour plots for different properties would provide beneficial guidance for designing new potent congeners.     

Exploring three-dimensional quantitative structural activity relationship (3D-QSAR) analysis of SCH 66336 (Sarasar) analogues of farnesyltransferase inhibitors

3D-QSAR analysis of a set of 37 analogues of SCH 66336 (Sarasar) was performed by most widely used computational tool, molecular field analysis (MFA) to investigate the substitutional requirements for the favorable receptor-drug interaction and to derive a predictive model that may be used for the designing of a novel farnesyltransferase inhibitors (FTIs). Regression analysis was carried out using genetic partial least squares (G/PLS) method. A highly predictive and statistically significant model was generated. The predictive ability of the model developed was assessed using a test set of six compounds (r(2)(pred) as high as 0.791). The analyzed MFA model has demonstrated a good fit, having r(2) value of 0.967 and cross-validated coefficient r(2)(cv) value as 0.921.