Three-dimensional quantitative structure: activity relationship studies on diverse structural classes of HIV-1 integrase inhibitors using CoMFA and CoMSIA

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques, were applied to a set of 89 HIV-1 integrase (IN) inhibitors (training set=61, test set=28), belonging to 11 structurally different classes. The biological data for 3' processing mechanism were used. For CoMFA calculations, three different fitting methods for alignment process were investigated. The best CoMFA model yielded the cross-validated r(2) r(2)(cv) =0.698 and the non-cross-validated r(2) (r(2))=0.947. The derived model indicated the importance of steric (60.8%) as well as electrostatic (39.2%) contributions. For CoMSIA calculations, different combinations of the fields were tested. The best CoMSIA model gave r(2)(cv) =0.724 and r(2)=0.864. This model showed that steric (30.3%), hydrogen bond donor (43.4%) and hydrogen bond acceptor (26.3%) properties played major roles in HIV-1 IN inhibition. The mapping of hydrogen bond interaction fields with the HIV-1 IN active site gave details on hydrogen bond forming between ligands and enzyme. These obtained results agree well with the experimental observations that there should be hydrogen bond interactions between ligands and Glu152, Lys156 and Lys159 residues. The results not only lead to a better understanding of structural requirements of HIV-1 IN inhibitors but also can help in the design of new IN inhibitors.     

3D-QSAR with the aid of pharmacophore search and docking-based alignments for farnesyltransferase inhibitors

Farnesyltransferase is a potential drug target for treating various types of cancers. Three-dimensional quantitative structure–activity relationships (3D-QSAR) for a series of farnesyltransferase inhibitors were investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Pharmacophore search and molecular docking methods were used for construction of the molecular alignments. While the 3D-QSAR models were created for a training set of 33 compounds, their external predictivity was proven using a test set of 12 compounds. The results provided a comprehensive insight into the relationship between the structural features and the activities of farnesyltransferase inhibitors. This investigation will facilitate optimization of the design of new potential farnesyltransferase inhibitors.     

Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: synthesis, biological evaluation and molecular modeling studies

Continuous efforts in microwave-assisted synthesis and the structure-activity relationships' (SARs) studies of novel modified 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitriles, allowed identification of new amidine and imidate derivatives as potent and dual CDK1/GSK-3 inhibitors. Combination of lead optimization and molecular modeling studies allowed identification of a dual CDK1/GSK-3 inhibitor (compound 13d) with submicromolar values.     

Solvatochromism, DNA binding, antitumor activity and molecular modeling study of mixed-ligand copper(II) complexes containing the bulky ligand: bis[N-(p-tolyl)imino]acenaphthene

Four mixed-ligand copper(II) complexes of the nitrogen ligand bis[N-(p-tolyl)imino]acenaphthene 1 (p-Tol-BIAN). These complexes, namely [Cu(p-Tol-BIAN)2](ClO4)2 2, [Cu(p-Tol-BIAN)(acac)](ClO4) 3, [Cu(p-Tol-BIAN)Cl2] 4 and [Cu(p-Tol-BIAN)(AcOH)(2)](ClO4)2 5, were prepared and characterized. Solvatochromism of the novel copper complexes in various solvents has been studied. Molecular mechanics (MM+) and molecular dynamic simulations have been performed to learn more about the solvatochromic behaviour and the DNA binding affinity of these complexes.     

Markers of fetal growth and serum levels of insulin-like growth factor (IGF) I, -II and IGF binding protein 3 in adults

Fetal growth has been linked with increased risk of cancer and cardiovascular disease later in life. The insulin-like growth factor (IGF) axis has recently been proposed as a predictor of risk of subsequent cancer and cardiovascular disease. However, only few data are available on the possible association between fetal growth and levels of IGFs later in life. We examined the association between markers of fetal growth, i.e. birth weight, birth length and Ponderal Index, from birth records and serum IGF-I, IGF-II, and IGF binding protein 3 (IGFBP-3) levels in 545 middle-aged Danish men and women. We fitted separate multivariate models including birth weight, birth length, Ponderal Index and serum IGF-I, IGF-II, and IGFBP-3, respectively. After adjustment for age, alcohol intake, smoking, diabetes mellitus, systolic and diastolic blood pressure, serum total cholesterol and current height and weight, we found negative associations between birth weight and Ponderal Index, respectively, and serum IGF-II in men, i.e. the mean regression coefficients were -49.41 (95% CI: -87.06-11.77) (microg/l)/kg and -3.49 (95% CI: -6.73-0.25) (microg/l)/(kg/m3), respectively. Furthermore, in men birth weight was negatively associated with the (IGF-I + IGF-II)/IGFBP-3 and IGF-II/IGFBP-3 ratios, which are believed to be indicators of bioavailable IGF and IGF-II, respectively. However, no other associations were found in any of the models. Between 1 and 16% of the variance in serum IGF-I, IGF-II, and IGFBP-3, respectively, could be explained by the statistical models used in the analyses. We found very little support to the hypothesis of an association between fetal growth and the IGF axis throughout life.     

Tyrosyl-tRNA synthetase inhibitors as antibacterial agents: synthesis, molecular docking and structure-activity relationship analysis of 3-aryl-4-arylaminofuran-2(5H)-ones

Thirty-five 3-aryl-4-arylaminofuran-2(5H)-one derivatives were designed, prepared and tested for their inhibitory activity against tyrosyl-tRNA synthetase. Out of these compounds, 3-(3-bromophenyl)-4-(3,5-dichlorophenylamino)furan-2(5H)-one (35) was the most active with IC₅₀ of 0.09 ± 0.02 μM. The structure-activity relationship revealed that introduction of chlorine atoms at both meta positions of aniline moiety significantly increased the enzyme inhibitory activity. The results of antibacterial assay revealed that the tested compounds showed good activity against Gram-positive bacteria, with 35 being the most potent with MIC₅₀ of 0.06 μg/mL against Staphylococcus aureus ATCC 25923. Molecular docking of 35 into S. aureus tyrosyl-tRNA synthetase active site was also performed. The inhibitor snugly fitting the active site may well explain its excellent inhibitory activity.     

Pharmacophore modeling and virtual screening for the discovery of new transforming growth factor-β type I receptor (ALK5) inhibitors

Inhibitors of transforming growth factor-β Type I Receptor (ALK5) have been thought as potential drugs for the treatment of fibrosis and cancer and a considerable number of ALK5 inhibitors have been reported recently. In order to clarify the essential structure–activity relationship for the known ALK5 inhibitors as well as identify new lead compounds against ALK5, 3D pharmacophore models have been established based on the known ALK5 inhibitors. The best pharmacophore model, Hypo1, was used as a 3D search query to perform a virtual screening. The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking studies to refine the retrieved hits. Finally a total of 100 compounds were obtained and some of them were selected for further in vitro and in vivo assay studies.     

Areas of decrement in health-related quality of life (HRQL): Comparing the SF-12, EQ-5D,and HUI 3

Background: Different measures of health status and health-related quality of life (HRQL) have been advocated for different purposes at the clinical and population level. Relatively little is known about how these measures function in relationship to one another. We examined the relationship between the Short-Form 12 (SF-12), EQ-5D, and Health Utilities Index (HUI) Mark 3 for overall scores and in analogous domains of health. A convenience sample was obtained through surveying patients at an inner-city community health center. Measurements and main results: The sample was comprised primarily of low-income racial/ethnic minorities; 393 patients were approached and 301 patients (77%) participated. The three measures had correlations between overall scores that ranged from 0.41 to 0.69 and correlations between similar domains from different measures that ranged from 0.42 to 0.59. For the HUI 3, any impairment most frequently was noted with pain, vision, cognition, and emotion. For the EQ-5D, pain/discomfort and anxiety/depression were reported as impaired most often. Compared to published population scores, participants reported impairments with increased frequency and at a greater level. Conclusions: Participants demonstrated consistency with responses to similar types of items and correlations between related aspects of health were moderate to strong. Domains of health most often reported as impaired resembled those noted in national surveys. Despite differences in the structure of the measures, all three instruments capture information about decrements in broadly analogous domains of health.     

Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives

A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K_Is in the range of 0.089-251 μM, whereas toward hCA II, K_Is = 50.5-487 nM. Isozyme hCA IX was inhibited with K_Is in the range of 5.2-18.3 nM, while hCA XII with K_Is = 6.0-16.4 nM, and hCA XIV with K_Is = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with K_Is = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K_Is = 24-50 nM).