3D-QSAR and molecular docking studies on 3-anilino-4-arylmaleimide derivatives as glycogen synthase kinase-3β inhibitors

Glycogen synthase kinase-3, a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders, and Alzheimer's disease. It is important to inhibit glycogen synthase kinase-3 selectively, and the net effect of the glycogen synthase kinase-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure-activity relationship studies on novel class of 3-anilino-4-arylmaleimide derivatives to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for the alignment of the molecules. Statistically significant CoMSIA (r2(cv)=0.614, r2(ncv)=0.948) and comparative molecular field analysis (r2(cv) =0.652, r2(ncv)=0.958) models were generated using 57 molecules in training set. The predictive ability of CoMSIA and comparative molecular field analysis models was determined using a test set of 17 molecules, which gave predictive correlation coefficients (r2(pred)) of 0.87 and 0.82, respectively, indicating good predictive power. Based on the information derived from CoMSIA and comparative molecular field analysis contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new anilinoarylmaleimide derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems, hence suggesting that newly designed molecules can be more potent and selective toward glycogen synthase kinase-3β inhibition.     

Prospective atom-based 3D-QSAR model prediction,pharmacophore generation,and molecular docking study of carbamate derivatives as dual inhibitors of AChE and MAO-B for Alzheimer’s disease

Carbamates are well known for AChE as well as MAO inhibition. In this study, atom-based 3D-QSAR model generation, virtual screening, and molecular docking studies were performed for a known series of 31 carbamate derivatives. The best hypothesis yielded four different pharmacophoric features with statistically significant 3D-QSAR model (correlation coefficient of R ² = 0.994 for training set molecules and very good predictive powers with Q ² and Pearson-R were 0.60 and 0.91, respectively). By virtual screening done against Schrödinger database, we identified 11 distinct drug-like molecules binding to both targets AChE and MAO-B efficiently. This generated 3D-QSAR hybrid model for dual enzymes provides basis for new structural scaffold would serve as building blocks in designing drug-like molecules for Alzheimer’s disease.     

3D-QSAR pharmacophore modeling and in silico screening of phospholipase A2α inhibitors

Cytosolic phospholipase A_2α have emerged as an attractive target for the development of analgesic and anti-inflammatory drugs. 3D-QSAR pharmacophore model was developed, based on previously reported 28 indole-5-carboxylic acids, and used to understand the structural factors affecting the inhibitory potency of these derivatives. Hydrogen bond acceptor, negative charge, and aromatic effects contribute to the inhibitory activity. The model was employed as a 3D search query to screen SPECS database to select new scaffolds. Finally, docking studies lead to the identification of fourteen potential phospholipase A_2α inhibitors. Subsequent ADME studies revealed the pharmacokinetic efficiency of these compounds.     

A 3D-QSAR study of catechol-O-methyltransferase inhibitors using CoMFA and CoMSIA

应用CoMFA方法和CoMSIA方法研究儿茶酚转甲基酶抑制剂的三维定量构效关系@艾纯芝$Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Graduate School of the Chinese Academy of Sciences!457 Zhongshan Road, Dalian 116023, Liaoning,China     

3D-QSAR study of tyrosine and propanoic acid derivatives as PPARα/γ dual agonists using CoMSIA

The peroxisome proliferator-activated receptors (PPARs) have increasingly become attractive targets for developing novel therapeutics for Type 2 Diabetes. Three dimensional-quantitative structure–activity relationship approach has been applied to a series of α-substituted 3-phenylpropanoic acid and tyrosine derivatives, reported as PPARα/γ dual agonists. Comparative molecular similarity indices analysis has been employed in correlating pharmacological data available for single enantiomer at individual receptor subtype. Three models: PPARα, PPARγ and PPARdual-model, using sum of individual activities as dependent parameter, are developed with statistically significant r _cv ²  > 0.5 and r _ncv ²  > 0.9 and lower values of standard error of estimation. This information can be used to design and prediction of enantioselective novel PPAR agonists. Activities of two sets of designed new molecules have also been predicted using generated models.     

Three-dimensional QSAR and pharmacophore mapping of biphenyl benzoic acid derivatives as selective human β3-adrenergic receptor agonists

Molecular modeling studies were performed to develop a predictive common pharmacophore hypothesis (CPH) and use it for alignment in three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies using CoMFA and CoMSIA, with a diverse set of 80 β₃-adrenergic receptor (β₃-AR) agonists. Using PHASE (Pharmacophore Alignment and Scoring Engine) six-point CPH with one acceptor, one negative charge, one positive charge, and three rings, features were derived for pharmacophore-based alignment of molecules. CPH was selected by correlating the observed and estimated activity for the training set and test set of molecules using partial least squares analysis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good “predictive” r ² value of 0.6635 and 0.8665 for CoMFA and CoMSIA, respectively. The 3D contour CoMFA/CoMSIA maps provided an interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects at different positions of the biphenyl benzoic acid derivatives. CPH can also provide a powerful template for virtual screening and design of new β₃-AR agonists.     

Identification of novel bacterial RNA polymerase “Switch Region” inhibitors using pharmacophore model based on multi-template and similarity research

Bacterial RNA polymerase, which is a complex molecular machine for RNA synthesis in all cellular organisms, appears to be a new discovered and potential protein. Switch Region of bacterial RNA polymerase turns out to be an ideal target for antibiotics in consequence of highly conserved in gram-positive/negative bacterial and non-conserved in human RNAP. Present study collected recently discovered bacterial RNAP inhibitors and generated a pharmacophore query in combination with similarity research for new antibiotics identification. The generated query is consisted of three features: one hydrophobic site and two acceptor atoms. Then, pharmacophore and similarity research as two different strategies were used against to 1,623,646 compounds from ZINC database. Finally, ten compounds were filtered out as potential antibiotics. This work could be less limitation in various scaffold research and more accuracy in antibiotics discovery by applying novel inhibitors.     

3D-QSAR CoMFA and CoMSIA studies on a set of diverse ��1a-adrenergic receptor antagonists

The α-adrenergic receptors (α-ARs) modulate a number of intracellular processes and among these α_1a-adrenergic receptors play an important role in the regulation of physiological processes related to cardiovascular system. In view of its therapeutic potential, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were performed on a set of diverse α-AR antagonists to understand the structural factors affecting their antagonistic activity where both CoMFA (q _train² = 0.709, r _train² = 0.962, and r _predictive² = 0.629) and CoMSIA (q _train² = 0.648, r _train² = 0.949, and r _predictive² = 0.656) models gave statistical significant results. The generated CoMFA and CoMSIA models suggest that steric, electrostatic and hydrophobic interactions play an important role in describing the variation in antagonistic activity. Therefore, the models may be useful in the identification and optimization of novel scaffolds with potent α_1a-adrenergic receptor antagonistic activity.     

Synergistic effects of interleukin-1β and interleukin-17A antibodies on collagen-induced arthritis mouse model

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that mainly causes the synovial joint inflammation and cartilage destruction. Both interleukin-1β (IL-1β) and Interleukin-17 (IL-17) are important proinflammatory cytokines involved in the pathogenesis of RA. We investigated whether combination therapy with IL-1β and IL-17A antibodies would generate the potential for synergistic effects on a collagen-induced arthritis (CIA) mouse model. Mice with CIA were subcutaneously injected with humanized IL-1β antibody, IL-17A antibody, or combination treatment. The effects of treatment were determined by arthritis severity score, histological damage and bone destruction, autoreactive humoral and cellular immune responses and cytokine production. Treatment with IL-1β antibody or IL-17A antibody alone resulted in beneficial effects on clinical and histological parameters of CIA mice. Compared with the single antibody treatments, the combination therapy resulted in a more significant effect in alleviating the severity of arthritis by preventing bone damage and cartilage destruction, reducing humoral and cellular immune responses, and down-regulating the expression of IL-1β, IL-6, IL-17A, IFN-γ, RANKL and MMP-3 in inflammatory tissue. In conclusion, combination treatment with humanized IL-1β and IL-17A antibodies demonstrates synergistic beneficial effects for preventing joint inflammation and cartilage destruction and bone damage in CIA mice model. These studies also provide evidence that combination with IL-1β and IL-17A antibodies may lead to a new combinatorial therapy for RA patients.     

Cultured cerebellar granule neurons as an in vitro aging model: Topoisomerase IIβ as an additional biomarker in DNA repair and aging

Aging in the brain is a multicellular process manifesting as neurodegeneration and associated functional impairment. In the present study, we report that cerebellar granule neurons (CGNs) in culture show senescence-mediated molecular changes indicating establishment of aging processes in vitro. CGNs were viable for 5 weeks followed by cellular degeneration. Molecular changes correlated with cellular senescence and aging include the elevation of senescence-mediated beta galactosidase (SA-β-gal) activity and intracellular Ca²⁺ levels. Decreased base excision repair (BER) as well as non-homologous end joining (NHEJ) activities in CGNs were also observed upon aging in vitro. The decrease in NHEJ activity was shown correlated with corresponding decrease in the levels of topoisomerase IIβ (topo IIβ), Ku 70 and Ku 80 suggesting a crucial role for topo IIβ in repair capacity of CGNs. These studies, besides establishing that CGNs would serve as a good in vitro model for analysis of aging phenomena, also brought out that topo IIβ, by virtue of its significant role in controlling NHEJ activity, would serve as an additional biomarker for studying aging process.     

Mode of action and dose–response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose–response behavior of key events, alteration of the dose–response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.     

Early effects of mood stabilizers on the Akt/GSK-3β signaling pathway and on cell survival and proliferation

Rationale  Lithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed. Objectives  We evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3β axis, this pathway was explored for other drugs. Materials and methods  The SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3β mRNA and protein were assessed for the seven drugs as well. Results  Lithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3β phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3β, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3β axis. Conclusion  Valproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3β axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis.     

4-Nitrophenol induces Leydig cells hyperplasia,which may contribute to the differential modulation of the androgen receptor and estrogen receptor-α and -β expression in male rat testes

4-Nitrophenol (PNP) is generally regarded as an environmental endocrine disruptor capable of estrogenic and anti-androgenic activities. To investigate PNP-induced reproductive effects, immature male rats were injected subcutaneously with PNP (0.1, 1, 10 mg/kg body weight or vehicle) daily for 4 weeks. We assessed reproductive tract alterations, sex hormone balance in the serum and estrogen receptor (ER)-α, -β and androgen receptor (AR) expression in testes. Although no significant difference was observed in body weight or testes weights of PNP-treated rats compared with the controls, the serum concentrations of testosterone in the 10 mg/kg PNP-treated group were significantly elevated. This effect was accompanied by Leydig cells hyperplasia in the testes. Conversely, there was a significant decrease in estradiol concentration and aromatase expression in the testes of the 10 mg/kg PNP-treated group. Furthermore, we observed a significant increase in ERα expression in the testes of the 10 mg/kg PNP-treated group compared with the control group. Conversely, ERβ expression displayed a significant reduction. Moreover, AR expression was significantly increased in the 10 mg/kg PNP-treated group compared with the control group. The existence of AR, ER-α and -β in the testes suggests that estradiol and testosterone directly affect germ cells and that differential modulation of AR, ER-α and -β in the testis may be involved in the direct effects of PNP or either the indirect effects of PNP-induced disruption of the estradiol-to-testosterone balance or the Leydig cells hyperplasia. Thus, the measurement of many endpoints is necessary for good risk assessment.     

Experimental study of midazolam as probe on evaluating activity of inhibited hepatic CYP3A

AIM To study the effect of ketoconazole (KTZ), a selective inhibitor of CYP3A, on in vivo and in vitro metabolic activity of hepatic CYP3A in rat with midazolam (MDZ) as probe, which was assessed by pharmacokinetic parameters of MDZ., and to establish a suitable marker or indicator for estimating drugmetabolizing activity of hepatic CYP3A. METHODS 1. In vivo study: Several loading doses of KTZ prepared in a mixture of PEG400 and propylene glycol (9:1) were administrated through rat sublingual vein followed by constant infusion at different rates through tail vein with an attempt to achieve corresponding steady-state plasma concentrations in order to attain continuous inhibition on CYP3A.