Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 13 and 14 are representatives of a new class of highly potent non nucleoside type inhibitors of HIV-1 reverse transcriptase. To conduct SAR studies on these two lead compounds, 102 new analogues were prepared. Thirty-three compounds displayed nanomolar range activity in vitro against wild-type HIV-1, and among these, 18 were active against the 103N, Y181C, and Y188L mutant strains with IC50 values inferior to 1 microM. Evaluation of this group of analogues against an additional eight single [100I, 101E, 106A, 138K, 179E, 190A, 190S, 227C] and four double HIV mutant strains [100I + 103N, 101E + 103N, 103N + 181C, and 227L + 106A], which are often present in HIV infected patients, permitted the selection of eight compounds, 17x, 18b, 18c, 18f, 18g, 27, 30, and 42, which are globally more active than the lead molecules 13/14, emivirine and the currently used NNRTI, nevirapine. Further comparison of the 3'-CN-substituted benzoylpyridinone compound 18c, and the corresponding 3'-acrylonitrile-substituted analogue 30, to efavirenz, the reference molecule in anti-HIV therapy today, revealed that the pyridinone analogues displayed a superior inhibition profile in the in vitro cellular assay system. These results form a solid basis for continued optimization of the pyridinone series.
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PMID:4-benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents: optimization and in vitro evaluation against clinically important HIV mutant strains. 1548 87

A number of 2H-pyrrolo[3,4-b] [1,5]benzothiazepine derivatives (PBTAs) 7-25 and the related synthetic intermediates 3-pyrrolyl aryl sulfones (PASs) 26-32 were designed, synthesized and tested as potential anti-HIV-1 agents targeted at the reverse transcriptase (RT). The PBTAs were conceived as tricyclic analogs of nevirapine, pyrrolo[1,2-b] [1,2,5]benzothiadiazepine 5 (PBTD) and pyrrolo[2,1-d] [1,2,5]benzothiadiazepine 6, NNRTIs endowed with potent anti-HIV-1 activities. The majority of tested PBTAs were active against HIV-1-induced cytopathicity in MT-4 cells at concentrations ranging from 0.3 to 40 microM. In particular, compound 10 was the most potent derivative with EC50 = 0.3 microM, comparable to that of nevirapine used as reference drug. In the 3-pyrrolyl aryl sulfones (26-32) series only three sulfones were found active against HIV-1 replication cycle. The following preliminary SAR could be depicted for the title derivatives: i) the conformationally restrained PBTAs are more potent than the corresponding open counterparts (PASs); ii) the DMA group give the highest anti-HIV-1 potency in the PBTAs series; iii) PBTAs and the corresponding thiones are equipotent; iv) an unsubstituted amino group, as part of p-chloroanilino moiety, is a strong determinant for the antiviral activity in the PASs series. The most potent derivatives in cell-based assays were proven to target the RT in enzyme assays. Unfortunately, none of the test compounds inhibited the multiplication of clinically relevant drug-resistant viruses (mutants of HIV-1 carrying K103N and Y181C mutations) at concentrations lower than 30 microM. However, the good results obtained against replication of wt HIV-1, lead us to consider compound 10 as a lead compound for further investigation in this field. In particular, our efforts will be directed to modifications of 10 devoted to obtain new derivatives active against HIV-1 mutant strains.
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PMID:2H-Pyrrolo[3,4-b] [1,5]benzothiazepine derivatives as potential inhibitors of HIV-1 reverse transcriptase. 1591 Aug 11

A novel oxindole was discovered as an HIV non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Systematic structural modifications were carried out to establish its SAR. These modifications led to the identification of oxindoles with low nanomolar potency for inhibiting HIV replication. These novel and potent oxindoles could serve as advanced leads for further optimizations.
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PMID:Design, synthesis and biological evaluations of novel oxindoles as HIV-1 non-nucleoside reverse transcriptase inhibitors. Part I. 1648 Aug 65

A series of aryltetrazolylacetanilides was synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors on wild-type virus and on the clinically relevant K103N mutant strain. Extensive SAR investigation led to potent compounds, with nanomolar activity on K103N, and orally bioavailable in rats.
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PMID:Tetrazole thioacetanilides: potent non-nucleoside inhibitors of WT HIV reverse transcriptase and its K103N mutant. 1650 41

Nevirapine (Viramune) belongs to the first generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Its efficiency is limited by drug resistant mutations, such as K103N and Y181C, so, the aim of this work was to design novel nevirapine analogues insensitive to the K103N and Y181C HIV-1 RT. 360 Nevirapine derivatives were designed using a combinatorial library design approach and these compounds were docked into the binding pocket of mutant HIV-1 RT enzyme structures, using the GOLD program. 124 Compounds having a GoldScore higher than that of nevirapine (55.00 and 52.00 for K103N and Y181C mutants, respectively) were first retrieved and submitted to a topological analysis with the SILVER program. Consequently, 31 compounds presenting a significant percentage of the surfaces buried upon binding (>80%) and exhibiting hydrogen bonds to either N103 or C181 residues of the HIV-RT were selected. To ensure that these compounds had hydrogen bonding interaction to either N103 or C181 residues, their interaction energies were estimated by quantum chemical calculations (QCCs). Finally, QCCs represent an alternative method for performing post docking procedure.
SAR QSAR Environ Res 2006 Apr
PMID:Design of nevirapine derivatives insensitive to the K103N and Y181C HIV-1 reverse transcriptase mutants. 1664 57

A novel sulfanyltriazole was discovered as an HIV-1 non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Chemical modifications and molecular modeling studies were carried out to establish its SAR and understand its interactions with the enzyme. These modifications led to the identification of sulfanyltriazoles with low nanomolar potency for inhibiting HIV-1 replication and promising activities against selected NNRTI resistant mutants. These novel and potent sulfanyltriazoles could serve as advanced leads for further optimization.
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PMID:Synthesis and biological evaluations of sulfanyltriazoles as novel HIV-1 non-nucleoside reverse transcriptase inhibitors. 1678 Nov 49

A novel series of quinolones was discovered as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using a structure-based approach. The lead quinolones exhibited single digit nanomolar potency in the HIV-1 replication assays. The preliminary SAR of these quinolones was also established via systematic structural modifications. These novel and potent quinolones could serve as advanced leads for further optimization.
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PMID:Design, synthesis, and biological evaluations of novel quinolones as HIV-1 non-nucleoside reverse transcriptase inhibitors. 1678 37

A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation"), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on seven model systems; dihydrofolate reductase, Lck kinase, ribosome inactivating protein, L: -arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2.
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PMID:Electrostatic evaluation of isosteric analogues. 1684 6

Ligand- and structure-based design approaches have been applied to an extended series of 74 efavirenz compounds effectively inhibiting wild type (WT) and mutant type (K103N) HIV-1 reverse transcriptase (RT). For ligand-based approach, three dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA), were performed. The starting geometry of efavirenz was obtained from X-ray crystallographic data. The efavirenz derivatives were constructed and fully optimized by ab-initio molecular orbital method at HF/3-21G level. Reliable QSAR models for high predictive abilities were developed. Regarding WT and K103N inhibitions, CoMFA models with r2/cv = 0.651 and 0.678 and CoMSIA models with r2/cv = 0.662 and 0.743 were derived, respectively. The interpretation obtained from the models highlights different structural requirements for inhibition of WT and K103N HIV-1 RT. To elucidate potential binding modes of efavirenz derivatives in the binding pocket of WT and K103N HIV-1 RT, structure-based approach based on computational docking studies of selected efavirenz compounds were performed by using GOLD and FlexX programs. The results derived from docking analysis give additional information and further probe the inhibitor-enzyme interactions. The correlation of the results obtained from 3D QSAR and docking models validate each other and lead to better understanding of the structural requirements for the activity. Therefore, these integrated results are informative to provide key features and a helpful guideline for novel compound design active against HIV-1 RT.
SAR QSAR Environ Res 2006 Aug
PMID:Computer-aided molecular design of highly potent HIV-1 RT inhibitors: 3D QSAR and molecular docking studies of efavirenz derivatives. 1692 Jun 59

As part of a systematic SAR study on the 3-iodo-4-phenoxypyridinone 3 (IOPY) type non-nucleoside reverse transcriptase inhibitors, the analogues 4a-4z bearing different C-3 substituents were synthesized and evaluated for their anti-HIV activity against wild-type HIV-1 and four of the principal HIV mutant strains (K103N, Y181C, Y188L, and I100L). The results show that the 3-vinyl analogue 4j is the only compound which displays anti-HIV activity comparable to IOPY 3, and in this respect represents a possible back-up to this lead molecule.
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PMID:Structure-activity relationship in the 3-iodo-4-phenoxypyridinone (IOPY) series: The nature of the C-3 substituent on anti-HIV activity. 1715 17


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