Structure-Based Design of Novel Dihydroalkoxybenzyloxopyrimidine Derivatives as Potent Nonnucleoside Inhibitors of the Human Immunodeficiency Virus Reverse Transcriptase

Sudbeck, Elise A.; Chen, Mao; Vig, Renu; Venkatachalam, T. K.; Tuel‐Ahlgren, Lisa; Uckun, Fatih M.

doi:10.1128/aac.42.12.3225

Cited by 42 publications

(34 citation statements)

References 45 publications

(71 reference statements)

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“…Alternative simulations [33] involved the use of many crystal structure of complexed inhibitors, superimposing by their most stable regions, with the aim to create a composite map of the binding site. Molecular Dynamics, Monte Carlo and rotamer libraries methods [34,35] have also been tried with the aim of introducing at least partially flexibility in the receptor macromolecule.…”

Section: Induced Fit Dockingmentioning

confidence: 99%

Inside the Hsp90 inhibitors binding mode through induced fit docking

Lauria

Ippolito

Almerico

2009

Journal of Molecular Graphics and Modelling

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Section: Induced Fit Dockingmentioning

confidence: 99%

Inside the Hsp90 inhibitors binding mode through induced fit docking

Lauria

Ippolito

Almerico

2009

Journal of Molecular Graphics and Modelling

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“…The fine docking protocol (described in Table 1) combines algorithms already applied to other docking targets [70][71][72][73][74] and has been trained to model 17 ligand-protein complexes between L99A mutant lysozyme (comprising 15 apolar and 2 slightly polar ligands, as listed in Table 3). Some additional ligand-lysozyme L99A complexes and some non-binders listed by Morton et al [25] were not modelled since the ligands contained atom types for which the CVFF force field is not able to define partial charges.…”

Section: Resultsmentioning

confidence: 99%

Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation

Machicado

López-Llano

Cuesta‐López

et al. 2005

J Comput Aided Mol Des

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Proteins could be used to carry and deliver small compounds. As a tool for designing ligand binding sites in protein cores, a three-step virtual screening method is presented that has been optimised using existing data on T4 lysozyme complexes and tested in a newly engineered cavity in flavodoxin. The method can pinpoint, in large databases, ligands of specific protein cavities. In the first step, physico-chemical filters are used to screen the library and discard a majority of compounds. In the second step, a flexible, fast docking procedure is used to score and select a smaller number of compounds as potential binders. In the third step, a finer method is used to dock promising molecules of the hit list into the protein cavity, and an optimised free energy function allows discarding the few false positives by calculating the affinity of the modelled complexes. To demonstrate the portability of the method, several cavities have been designed and engineered in the flavodoxin from Anabaena PCC 7119, and the W66F/L44A double mutant has been selected as a suitable host protein. The NCI database has then been screened for potential binders, and the binding to the engineered cavity of five promising compounds and three tentative non-binders has been experimentally tested by thermal up-shift assays and spectroscopic titrations. The five tentative binders (some apolar and some polar), unlike the three tentative non-binders, are shown to bind to the host mutant and, importantly, not to bind to the wild type protein. The three-step virtual screening method developed can thus be used to identify ligands of buried protein cavities. We anticipate that the method could also be used, in a reverse manner, to identify natural or engineerable protein cavities for the hosting of ligands of interest.

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“…A novel computer model of the NNI binding pocket of HIV-1 RT was constructed by superimposing nine individual RT-NNRTI crystal structures and generating a van der Waals surface that encompassed all the overlaid ligands [56,89,113,114]. This "composite binding pocket" revealed a different and unexpectedly larger NNRTI binding site than shown in or predictable from any of the individual structures and served as a probe to more accurately define the potentially usable space in the binding site (Fig.…”

Section: Rational Design Of Tight Binding Thiourea Nnrtismentioning

confidence: 99%

“…We hypothesized that NNRTI binding pocket model based on an individual RT-NNI crystal structure [36,43,51,76,86,91] would have limited potential for predicting the binding of new, chemically distinct inhibitors. To overcome this problem, a composite binding pocket or a composite molecular surface was constructed using the NNRTI binding site coordinates of multiple and varied RT-NNI structures [56,89,113,114]. The binding pocket generated from nine distinct RT-NNI complexes (HEPT, MKC, TNK, APA, NVP, N-ethyl NVP derivative, 8-Cl TIBO, and 9-Cl TIBO structures) revealed a larger than presumed NNI binding pocket not shown or predicted by any of the individual structures alone (Fig.…”

Section: Strategies For Design and Synthesis Of Novel Thiourea Nnrtismentioning

confidence: 99%

Novel Broad-Spectrum Thiourea Non-Nucleoside Inhibitors for the Prevention of Mucosal HIV Transmission

D’Cruz

Uckun²

2006

CHR

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Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTI) are an integral part of combination therapy comprising three classes of antiretroviral drugs for the management of HIV/AIDS. NNRTIs are chemically diverse compounds that bind to a common allosteric site of HIV-1 RT and noncompetitively inhibit DNA polymerization. Resistance to NNRTIs arises rapidly upon drug treatment and results from mutation of the amino acids lining the HIV-1 RT binding pocket. Nevertheless, rationally designed NNRTIs deduced from changes in binding pocket size, shape, and residue character that result from clinically observed NNRTI resistance mutations exhibit broad-spectrum anti-HIV-1 activity. Notably, membrane permeable tight binding NNRTIs have utility as topical microbicides since they are capable of blocking cell-free and cell-associated mucosal HIV-1 infection without metabolic activation. This review summarizes the discovery of highly potent tight binding phenethyl-thiazolyl-thiourea (PETT) derivatives targeting the NNI binding pocket of HIV-1 RT. These NNRTIs were rationally designed by molecular docking using a composite binding pocket constructed by superimposing the crystal structure coordinate data of several NNI/RT ligand-binding site complexes. Molecular modeling and score functions such as molecular surface area, the buried surface, and binding affinity values were used to analyze how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up of these NNRTIs, and how these changes could affect drug binding. Several ligand derivatization sites were identified for docked compounds that fit the binding pocket. The best fit was determined by calculating an inhibition constant (Ludi Ki) of the docked compound for the composite binding pocket. Compounds with a Ludi Ki of <1 microM were identified as the most promising tight binding NNRTIs. This review highlights novel lipophilic thiourea NNRTIs that display high binding affinity and selective indices with robust anti-HIV-1 activity against the wild type as well as drug-resistant isolates carrying multiple RT gene mutations. The increasing prevalence of drug-escape mutants among recent HIV seroconverters makes the discovery of these broad-spectrum thiourea NNRTIs useful as a component of topical microbicide for the prevention of mucosal HIV transmission.

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Structure-Based Design of Novel Dihydroalkoxybenzyloxopyrimidine Derivatives as Potent Nonnucleoside Inhibitors of the Human Immunodeficiency Virus Reverse Transcriptase

Cited by 42 publications

References 45 publications

Inside the Hsp90 inhibitors binding mode through induced fit docking

Inside the Hsp90 inhibitors binding mode through induced fit docking

Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation

Novel Broad-Spectrum Thiourea Non-Nucleoside Inhibitors for the Prevention of Mucosal HIV Transmission

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