Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In many cases at the beginning of an HTS-campaign, some information about active molecules is already available. Often known active compounds (such as substrate analogues, natural products, inhibitors of a related protein or ligands published by a pharmaceutical company) are identified in low-throughput validation studies of the biochemical target. In this study we evaluate the effectiveness of a support vector machine applied for those compounds and used to classify a collection with unknown activity. This approach was aimed at reducing the number of compounds to be tested against the given target. Our method predicts the biological activity of chemical compounds based on only the atom pairs (AP) two dimensional topological descriptors. The supervised support vector machine (SVM) method herein is trained on compounds from the MDL drug data report (MDDR) known to be active for specific protein target. For detailed analysis, five different biological targets were selected including cyclooxygenase-2, dihydrofolate reductase, thrombin, HIV-reverse transcriptase and antagonists of the estrogen receptor. The accuracy of compound identification was estimated using the recall and precision values. The sensitivities for all protein targets exceeded 80% and the classification performance reached 100% for selected targets. In another application of the method, we addressed the absence of an initial set of active compounds for a selected protein target at the beginning of an HTS-campaign. In such a case, virtual high-throughput screening (vHTS) is usually applied by using a flexible docking procedure. However, the vHTS experiment typically contains a large percentage of false positives that should be verified by costly and time-consuming experimental follow-up assays. The subsequent use of our machine learning method was found to improve the speed (since the docking procedure was not required for all compounds from the database) and also the accuracy of the HTS hit lists (the enrichment factor).
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PMID:Target specific compound identification using a support vector machine. 1734 18

A new GRID-based method for scaffold hopping (SHOP) is presented. In a fully automatic manner, scaffolds were identified in a database based on three types of 3D-descriptors. SHOP's ability to recover scaffolds was assessed and validated by searching a database spiked with fragments of known ligands of three different protein targets relevant for drug discovery using a rational approach based on statistical experimental design. Five out of eight and seven out of eight thrombin scaffolds and all seven HIV protease scaffolds were recovered within the top 10 and 31 out of 31 neuraminidase scaffolds were in the 31 top-ranked scaffolds. SHOP also identified new scaffolds with substantially different chemotypes from the queries. Docking analysis indicated that the new scaffolds would have similar binding modes to those of the respective query scaffolds observed in X-ray structures. The databases contained scaffolds from published combinatorial libraries to ensure that identified scaffolds could be feasibly synthesized.
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PMID:SHOP: scaffold HOPping by GRID-based similarity searches. 1748 78

The impact of 2'-deoxy-2'-fluoroarabinonucleotide residues (2'F-araN) on different G-quadruplexes derived from a thrombin-binding DNA aptamer d(G2T2G2TGTG2T2G2), an anti-HIV phosphorothioate aptamer PS-d(T2G4T2) and a DNA telomeric sequence d(G4T4G4) via UV thermal melting (T(m)) and circular dichroism (CD) experiments has been investigated. Generally, replacement of deoxyguanosines that adopt the anti conformation (anti-guanines) with 2'F-araG can stabilize G-quartets and maintain the quadruplex conformation, while replacement of syn-guanines with 2'F-araG is not favored and results in a dramatic switch to an alternative quadruplex conformation. It was found that incorporation of 2'F-araG or T residues into a thrombin-binding DNA G-quadruplex stabilizes the complex (DeltaT(m) up to approximately +3 degrees C/2'F-araN modification); 2'F-araN units also increased the half-life in 10% fetal bovine serum (FBS) up to 48-fold. Two modified thrombin-binding aptamers (PG13 and PG14) show an approximately 4-fold increase in binding affinity to thrombin, as assessed via a nitrocellulose filter binding assay, both with increased thermal stability (approximately 1 degrees C/2'F-ANA modification increase in T(m)) and nuclease resistance (4-7-fold) as well. Therefore, the 2'-deoxy-2'-fluoro-d-arabinonucleic acid (2'F-ANA) modification is well suited to tune (and improve) the physicochemical and biological properties of naturally occurring DNA G-quartets.
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PMID:G-quadruplex induced stabilization by 2'-deoxy-2'-fluoro-D-arabinonucleic acids (2'F-ANA). 1763 49

Bile salt-dependent lipase (BSDL) is an enzyme involved in the duodenal hydrolysis and absorption of cholesteryl esters. Although some BSDL is transported to blood, the role of circulating BSDL is unknown. Here, we demonstrate that BSDL is stored in platelets and released upon platelet activation. Because BSDL contains a region that is structurally homologous to the V3 loop of HIV-1, which binds to CXC chemokine receptor 4 (CXCR4), we hypothesized that BSDL might bind to CXCR4 present on platelets. In human platelets in vitro, both BSDL and a peptide corresponding to its V3-like loop induced calcium mobilization and enhanced thrombin-mediated platelet aggregation, spreading, and activated alpha(IIb)beta(3) levels. These effects were abolished by CXCR4 inhibition. BSDL also increased the production of prostacyclin by human endothelial cells. In a mouse thrombosis model, BSDL accumulated at sites of vessel wall injury. When CXCR4 was antagonized, the accumulation of BSDL was inhibited and thrombus size was reduced. In BSDL(-/-) mice, calcium mobilization in platelets and thrombus formation were attenuated and tail bleeding times were increased in comparison with those of wild-type mice. We conclude that BSDL plays a role in optimal platelet activation and thrombus formation by interacting with CXCR4 on platelets.
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PMID:Bile salt-dependent lipase interacts with platelet CXCR4 and modulates thrombus formation in mice and humans. 1803 96

We introduce human proteome-derived, database-searchable peptide libraries for characterizing sequence-specific protein interactions. To identify endoprotease cleavage sites, we used peptides in such libraries with protected primary amines to simultaneously determine sequence preferences on the N-terminal (nonprime P) and C-terminal (prime P') sides of the scissile bond. Prime-side cleavage products were tagged with biotin, isolated and identified by tandem mass spectrometry, and the corresponding nonprime-side sequences were derived from human proteome databases using bioinformatics. Identification of hundreds to over 1,000 individual cleaved peptides allows the consensus protease cleavage site and subsite cooperativity to be readily determined from P6 to P6'. For the highly specific GluC protease, >95% of the 558 cleavage sites identified displayed the canonical selectivity. For the broad-specificity matrix metalloproteinase 2, >1,200 peptidic cleavage sites were identified. Profiling of HIV protease 1, caspase 3, caspase 7, cathepsins K and G, elastase and thrombin showed that this approach is broadly applicable to all mechanistic classes of endoproteases.
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PMID:Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites. 1853 87

Virtual screening performance of support vector machines (SVM) depends on the diversity of training active and inactive compounds. While diverse inactive compounds can be routinely generated, the number and diversity of known actives are typically low. We evaluated the performance of SVM trained by sparsely distributed actives in six MDDR biological target classes composed of a high number of known actives (983-1645) of high, intermediate, and low structural diversity (muscarinic M1 receptor agonists, NMDA receptor antagonists, thrombin inhibitors, HIV protease inhibitors, cephalosporins, and renin inhibitors). SVM trained by regularly sparse data sets of 100 actives show improved yields at substantially reduced false-hit rates compared to those of published studies and those of Tanimoto-based similarity searching method based on the same data sets and molecular descriptors. SVM trained by very sparse data sets of 40 actives (2.4%-4.1% of the known actives) predicted 17.5-39.5%, 23.0-48.1%, and 70.2-92.4% of the remaining 943-1605 actives in the high, intermediate, and low diversity classes, respectively, 13.8-68.7% of which are outside the training compound families. SVM predicted 99.97% and 97.1% of the 9.997 M PUBCHEM and 167K remaining MDDR compounds as inactive and 2.6%-8.3% of the 19,495-38,483 MDDR compounds similar to the known actives as active. These suggest that SVM has substantial capability in identifying novel active compounds from sparse active data sets at low false-hit rates.
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PMID:Evaluation of virtual screening performance of support vector machines trained by sparsely distributed active compounds. 1853 44

In this study, we propose a drug design approach which includes docking, molecular fingerprints based cluster analysis, and 'induced' descriptors based receptor-dependent 3D-QSAR. The method was shown to be very useful for screening and modeling structurally diverse data sets of pharmacological interest. Different from other receptor-dependent 3D-QSAR, no ambiguous alignments are required for the construction of the models, and the computational cost is relatively lower. Moreover, 'induced' descriptors were shown to be very powerful in "capturing" ligand-receptor intermolecular interactions. The methodology was validated for eight data sets sampled from the literature and from public databases: human sex hormone-binding globulin, human corticosteroid-binding globulin, anthrax lethal factor, HIV-1 reverse transcriptase, neuraminidase A, thrombin, trypsin, and Pneumocystis carinii dihydrofolate reductase data sets. The resulting models were interpretable; the constructed QSAR equations have high statistical significance and predictive strength; and the drug design solutions were shown to be useful for guiding ligand modification for the development of new inhibitors for a broad range of molecular targets.
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PMID:Using molecular docking, 3D-QSAR, and cluster analysis for screening structurally diverse data sets of pharmacological interest. 1881 24

The resistance of HIV strains to the available antiretroviral medication has become a major problem in the world today. This has forced researchers to investigate the possible use of alternative drugs such as homeopathic medicine (e.g. immunomodulators) to enhance the immune system of patients infected with HIV. Canova is an immunomodulator of herbal origin which is known to stimulate the host defense against several pathological states through the activation of the immune system. Blood platelets play an important role in homeostasis, thrombosis and the immune response by forming platelet aggregates. The ultrastructure of platelet aggregates of patients with HIV has been studied previously using SEM to determine the effect of HIV on the platelet morphology. Membrane blebbing and ruptured platelet membranes were observed which is indicative of apoptosis, revealing that HIV patients may develop thrombocytopenia as a result of peripheral platelet destruction. The aim of the current study was to investigate the effect of HIV on the morphology of platelets from patients treated with the immuno-modulator, Canova, compared to control individuals and HIV patients not on the Canova treatment. Blood was drawn from the individuals and the coagula were formed by adding human thrombin to the platelet rich plasma. Examination was done using SEM. CD4 counts were also determined. Slight morphological changes were seen when comparing the fibrin networks from the control, untreated HIV patients and the Canova-treated HIV patients, suggesting that HIV does not impact on the fragility of fibrin networks. In HIV patients there are bleb-like bulges on the membrane of platelets as well as membrane breakages visible on the aggregate, whereas in the Canova-treated patients membrane blebbing is far less pronounced and there are large areas of intact, smooth membranes with visible canalicular areas, suggesting that Canova protects the membranes of platelets and that blebbing does not appear in such great proportions as was found in the untreated HIV group. These results support and provide ultrastructural evidence for the results seen in previous research, where it is seen that Canova protects the immune system of immuno-compromised patients by keeping the ultrastructure intact thereby preventing the devastating cyto-destructive effects of HIV disease.
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PMID:Investigating the ultrastructure of platelets of HIV patients treated with the immuno-regulator, Canova: a qualitative scanning electron microscopy study. 1922 42

Prophylactic administration of unfractionated heparin is a common practice in a perioperative period. Heparin monitoring with subcutaneous dosing is not recommended; however it becomes important in selected patients. We report a case of massive hemorrhage with subcutaneous heparin administration in an HIV-positive male patient with cachexia and mild liver dysfunction. Prolonged activated plasma thromboplastin time and thrombin time, but normal reptilase time well as response to protamine sulfate point towards the heparin effect. Inhibitor screen was negative and factor VIII activity was normal. All these rule out the possibility of acquired factor VIII inhibitor or any other inhibitor and confirm that this bleeding was due to heparin overdose. We believe that delayed clearance of UH secondary to possible involvement of reticuloendothelial system might have been be responsible for heparin overdose even though inadvertent administration of large dose of heparin intravenously can not be completely ruled out. Administration of unfractionated heparin to a patient with cachexia and abnormal liver function warrants close attention to heparin monitoring or switch to low molecular weight heparin since its mechanism of elimination differs.
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PMID:Life-threatening hemorrhage following subcutaneous heparin therapy. 1943 12

The prevalence, cause and the impact of antiphospholipid antibodies (APAs) on the clinical severity in haemophilia patients is poorly studied. We studied 72 severe seronegative (negative for HIV, HBsAg, HCV) haemophilia patients for the presence of four common APAs. Twenty-six (36.1%) were positive for any one of the APAs studied of which eight were positive only for anticardiolipin antibodies, three for beta2 glycoprotein (beta2GP1), four for prothrombin (PT) and six for anti annexin antibodies. Remaining six patients showed multi-specific antibodies. Further, clinically severe haemophilia patients (n = 37) showed higher prevalence of APAs as compared with the clinically milder group (n = 35) suggesting that these antibodies do not contribute in alleviating the clinical severity in haemophilia patients as has been observed with other inherited thrombophilia markers. The study of in vitro thrombin generation showed a higher endogenous thrombin potential (ETP) i.e. almost normal, in case of beta2GP1-positive patients as compared with patients with other types of APAs. High prevalence of APAs in clinically severe haemophilia patients may be a consequence of continuing tissue damage in the clinically severe group; as in India, clotting factor concentrates cannot be used ad lib because of financial constraints. Higher thrombin-generating potential in case of patients positive for beta2GP1 did not seem to have any impact on the clinical severity of haemophilia patients.
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PMID:Antiphospholipid antibodies in haemophilia patients with severe bleeding tendency: cause, consequence or a consequential cause? 1954 66


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