Drug binding

The presence of heterocyclic moiety in diverse compounds, strongly indicative of the desired effect on physiological activity, and it reflects on efforts to find useful synthetic drugs.

12p tocectocec 25-05-2020 19 2   Download

Single-crystal X-ray structure determinations of the complex between the minor-groove binder distamycin and d(GGCCAATTGG) reveal two 1 : 1 binding modes which differ in the orientation of the drug molecule in the minor groove. The two crystals were grown from different crystallization conditions and found to diffract to 2.38 and ˚ 1.85 A, respectively. The structures were refined to completion using SHELXL-93, resulting in a residual R factor of ˚ 20.30% for the 2.38-A resolution structure (including 46 ˚ water molecules) and 19.74% for the 1.

10p system191 01-06-2013 31 5   Download

Department of Chemistry ‘IFM’, University of Torino, Italy; 2Department of Biology, University ‘Roma Tre’, Rome, Italy; 3Department of Structural and Functional Biology, University of Insubria, Italy Haem binding to human serum albumin (HSA) endows the protein with peculiar spectroscopic properties. Here, the effect of ibuprofen and warfarin on the spectroscopic properties of ferric haem –human serum albumin (ferric HSA–haem) and of ferrous nitrosylated haem –human serum albumin (ferrous HSA –haem-NO) is reported.

7p system191 01-06-2013 47 3   Download

The cytochrome P450 family of enzymes has long been known tometabolize a wide range of compounds, including many of today’s most common drugs. A novel nuclear receptor called PXR has been established as an activator of several of the cytochrome P450 genes, including CYP3A4. This enzyme is believed to account for the metabolism of more than 50% of all prescription drugs. PXR is therefore used as a negative selector target and discriminatory filter in preclinical drug development.

9p research12 29-04-2013 45 3   Download

The structure–activity relations of a series of synthetic phenoxazone drugs with aminoalkyl side chains of variable length and different terminal groups were investigated by examining their biological activity and DNA complexation affinity. Biological activitywas determined fromtheir ability to induce apoptosis and cell cycle perturbations (activation of cell cycle checkpoints) using the human malignant MOLT-3 cell line. The thermodynamic parameters of drug– DNA complexation were determined by differential scan-ning calorimetry....

8p tumor12 20-04-2013 37 4   Download

HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8–2.3 A˚ resolution, and the inhibitory activity of the compounds characterized inorder toevaluate the effects of the individual modifications. ...

13p fptmusic 16-04-2013 44 3   Download

HIV-1 protease (PR) and two drug-resistant variants – PR with the V82A mutation (PRV82A) and PR with the I84V mutation (PRI84V) – were studied using reduced peptide analogs of five natural cleavage sites (CA-p2, p2-NC, p6 pol -PR, p1-p6 and NC-p1) to understand the structural and kine-tic changes. The common drug-resistant mutations V82A and I84V alter residues forming the substrate-binding site. Eight crystal structures were refined at resolutions of 1.10–1.60 A ˚ .

13p fptmusic 12-04-2013 39 2   Download

Plant flavonoids are polyphenolic compounds, commonly found in vegeta-bles, fruits and many food sources that form a significant portion of our diet. These compounds have been shown to interact with several ATP-bind-ing cassette transporters that are linked with anticancer and antiviral drug resistance and, as such, may be beneficial in modulating drug resistance. This study investigates the interactions of six common polyphenols; querce-tin, silymarin, resveratrol, naringenin, daidzein and hesperetin with the multidrug-resistance-associated proteins, MRP1, MRP4 and MRP5. ...

16p fptmusic 12-04-2013 40 2   Download

The structural changes produced by the minor-groove binding ligand DAPI (4¢,6-diamidine-2-phenylindole) on individual strands of trinucleotide repeat sequences were detectedby electrophoreticband-shift analysis andrelated to their effects on DNA replication in vitro. Among the 20 possible single-stranded trinucleotide repeats, only theT-rich strand of the AATÆATT triplet exhibits an observable fluorescence band and a change in electrophoretic mobility due to the drug binding.

7p fptmusic 12-04-2013 46 4   Download

The Hsp90 molecular chaperone catalyses the final activa-tion step of many of themost important regulatory proteins of eukaryotic cells. The antibiotics geldanamycin and rad-icicol act as highly selective inhibitors of in vivo Hsp90 function through their ability to bindwithin the ADP/ATP binding pocket of the chaperone. Drugs based on these compounds are now being developed as anticancer agents, their administration having the potential to inactivate sim-ultaneously several of the targets critical for counteracting multistep carcinogenesis. ...

7p fptmusic 12-04-2013 45 3   Download

HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such,HIV-1proteasehasbecomean important target for the treatment ofAIDS, and efficient drugs have beendeveloped. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different phar-macokinetic properties as well as new interaction patterns....

9p awards 05-04-2013 32 2   Download

The crystal structures of the wild-type HIV-1 protease (PR) and the two resistant variants, PRV82Aand PRL90M,have been determined in complex with the antiviral drug, indi-navir, to gain insight into the molecular basis of drug resistance. V82A and L90M correspond to an active site mutation and nonactive site mutation, respectively. The inhibition (Ki)of PRV82Aand PRL90Mwas 3.3- and 0.16-fold, respectively, relative to the value for PR. They showed only a modest decrease, of 10–15%, in theirkcat /Kmvalues relative to PR. ...

9p dell39 03-04-2013 28 3   Download

Human serum albumin (HSA), the most prominent protein in plasma, is best known for its exceptional capacity to bind ligands (e.g. heme and drugs). Here, binding of the anti-HIV drugs abacavir, atazanavir, didano-sine, efavirenz, emtricitabine, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, and zidovudine to HSA and ferric heme–HSA is reported.

10p dell39 27-03-2013 44 5   Download

Streptococcus pneumoniaeis one of the major pathogens worldwide. The use of currently available antibiotics to treat pneumococcal diseases is ham-pered by increasing resistance levels; also, capsular polysaccharide-based vaccination is of limited efficacy. Therefore, it is desirable to find targets for the development of new antimicrobial drugs specifically designed to fight pneumococcal infections.

13p inspiron33 23-03-2013 46 3   Download

Recently published genomic investigations of the human pathogenMyco-bacterium tuberculosishave revealed that genes coding the proteins involved in riboflavin biosynthesis are essential for the growth of the organism. Because the enzymes involved in cofactor biosynthesis pathways are not present in humans, they appear to be promising candidates for the develop-ment of therapeutic drugs.

15p inspiron33 23-03-2013 37 4   Download

Thymidine kinase (TK) is the key enzyme in salvaging thymidine to pro-duce thymidine monophosphate. Owing to its ability to phosphorylate nucleoside analogue prodrugs, TK has gained attention as a rate-limiting drug activator.

11p galaxyss3 21-03-2013 58 3   Download

ABCG2 confers resistance to cancer cells by mediating the ATP-dependent outward efflux of chemotherapeutic compounds. Recent studies have indi-cated that the protein contains a number of interconnected drug binding sites. The present investigation examines the coupling of drug binding to ATP hydrolysis.

9p galaxyss3 07-03-2013 46 4   Download

6-Phosphogluconate dehydrogenase is a potential target for new drugs against African trypanosomiasis. Phosphorylated aldonic acids are strong inhibitors of 6-phosphogluconate dehydrogenase, and 4-phospho-d-erythro-nate (4PE) and 4-phospho-d-erythronohydroxamate are two of the stron-gest inhibitors of theTrypanosoma bruceienzyme.

10p media19 05-03-2013 37 3   Download

Human serum albumin (HSA) has an extraordinary ligand-binding capac-ity, and transports Fe(III)heme and medium- and long-chain fatty acids. In human immunodeficiency virus-infected patients the administered drugs bind to HSA and act as allosteric effectors. Here, the binding of Fe(III)-heme to HSA in the presence of three representative anti-HIV drugs and myristate is investigated.

12p media19 04-03-2013 44 3   Download

Human P-glycoprotein is an ATP-binding cassette transporter that plays an important role in the defence against potentially harmful molecules from the environment. It is involved in conferring resistance against cancer therapeutics and plays an important role for the pharmacokinetics of drugs.

10p vinaphone15 27-02-2013 22 3   Download