Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking

Chen, H F; Dong, Xiao; Zen, B S; Gao, Kun; Yuan, Shuofeng; Panaye, Annick; Fan, Botao

doi:10.1080/1062936032000101493

Cited by 8 publications

(5 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Current strategies identify small molecule lead compounds that bind to protein targets by screening arrays of various sorts (56). Lead compounds are also identified upon the basis of predicted 3-D structures (57,58). Once the 3-D structure is determined, custom design of small molecules against selected domains can proceed.…”

Section: Discussionmentioning

confidence: 99%

Recombinant EWS-FLI1 Oncoprotein Activates Transcription

2004

View full text Add to dashboard Cite

The Ewing's sarcoma family of tumors (ESFT) contains a characteristic translocation the chimeric transcript of which is translated to become the EWS-FLI1 fusion protein. EWS-FLI1 regulates transcription and posttranscriptional splicing. Elimination of EWS-FLI1 protein from ESFT cells induces apoptosis and reduces xenograft tumor growth. Therefore the production of a biologically active recombinant EWS-FLI1 could lead to discoveries that would enhance our mechanistic understanding of ESFT. We have cloned, expressed, and purified a biologically active recombinant EWS-FLI1 in Escherichia coli using affinity column chromatography. A refolding procedure was required to render the recombinant EWS-FLI1 soluble in relatively native conditions. The structural alterations induced by the refolding procedure were monitored by SDS-gel electrophoresis, circular dichroism, and steady-state fluorescence spectroscopy. Recombinant EWS-FLI1 under native conditions approaches a largely unfolded conformation. Recombinant EWS-FLI1 protein under native conditions specifically binds to DNA and transcribes RNA. Our biologically active recombinant EWS-FLI1 oncoprotein will be useful to identify functional molecular partners and inhibitors.

show abstract

Section: Discussionmentioning

confidence: 99%

Recombinant EWS-FLI1 Oncoprotein Activates Transcription

2004

View full text Add to dashboard Cite

show abstract

“…Understanding the spatial relationship of functional groups of different molecules is necessary to develop three-dimensional (3D) pharmacophore hypotheses. Such hypotheses have been utilized in various aspects of drug design, such as structure−activity-relationship (SAR) rationalization and design, in silico screening, and scaffold hopping. − The development of a three-dimensional pharmacophore model involves the generation of conformations of molecules and overlaying them using algorithms to maximize an objective function such as shape, functional group, and property distribution overlap. There are a number of commercially available software packages which perform this task, including FlexS, ROCS, Catalyst, Seal, and MIMIC …”

Section: Introductionmentioning

confidence: 99%

Geometric Accuracy of Three-Dimensional Molecular Overlays

Chen

Higgs

Vieth

2006

J. Chem. Inf. Model.

View full text Add to dashboard Cite

This study examines the dependence of molecular alignment accuracy on a variety of factors including the choice of molecular template, alignment method, conformational flexibility, and type of protein target. We used eight test systems for which X-ray data on 145 ligand-protein complexes were available. The use of X-ray structures allowed an unambiguous assignment of bioactive overlays for each compound set. The alignment accuracy depended on multiple factors and ranged from 6% for flexible overlays to 73% for X-ray rigid overlays, when the conformation of the template ligand came from X-ray structures. The dependence of the overlay accuracy on the choice of templates and molecules to be aligned was found to be the most significant factor in six and seven of the eight ligand-protein complex data sets, respectively. While finding little preference for the overlay method, we observed that the introduction of molecule flexibility resulted in a decrease of overlay accuracy in 50% of the cases. We derived rules to maximize the accuracy of alignment, leading to a more than 2-fold improvement in accuracy (from 19% to 48%). The rules also allowed the identification of compounds with a low (<5%) chance to be correctly aligned. Last, the accuracy of the alignment derived without any utilization of X-ray conformers varied from <1% for the human immunodeficiency virus data set to 53% for the trypsin data set. We found that the accuracy was directly proportional to the product of the overlay accuracy from the templates in their bioactive conformations and the chance of obtaining the correct bioactive conformation of the templates. This study generates a much needed benchmark for the expectations of molecular alignment accuracy and shows appropriate usages and best practices to maximize hypothesis generation success.

show abstract

“…Because the electronegativity at position 3 have potent relationship with anti-HIV activity, we design a series of mono-, di-, and trisubstituted DCK analogues by taking into account of this factor, such as 3-nitromethyl (CH 2 NO 2 ), 3-cyanomethyl (CH 2 CN), 3-methylcarbamate (CH 2 OCONH 2 ), 3-hydroxymethyl (CH 2 OH) and halides (X). All designed new compounds, generated using previously developed structure generation system [38], were then predicted with SVM models for their activity against HIV replication, as shown in Table 4. The log P, HOMO and LUMO values were equally calculated with HYPERCHEM 7.0.…”

Section: Design Of New Compoundsmentioning

confidence: 99%

Computational Studies and Drug Design for HIV-1 Reverse Transcriptase Inhibitors of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-Khellactone (DCK) Analogs

Chen

Fan

Zhao

et al. 2005

J Comput Aided Mol Des

View full text Add to dashboard Cite

Molecular docking and molecular dynamics simulation were applied to study the binding mode of 3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs anti-HIV inhibitors with HIV-1 RT. The results suggest that there is a strong hydrogen bond between DCK O16 and NH of Lys101, and that DCK analogues might act similarly as other types of HIV-1 RT inhibitors. The investigation about drug resistance for DCK shows no remarkable influence on the most frequently observed mutation K103N of HIV-1 RT. Based on the proposed mechanism, some new structures were designed and predicted by a SVM model. All compounds exhibited potent inhibitory activities against HIV replication in H9 lymphocytes with EC50 values lower than 1.95 microM. The rationality of the method was validated by experimental results.

show abstract

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking

Cited by 8 publications

References 16 publications

Recombinant EWS-FLI1 Oncoprotein Activates Transcription

Recombinant EWS-FLI1 Oncoprotein Activates Transcription

Geometric Accuracy of Three-Dimensional Molecular Overlays

Computational Studies and Drug Design for HIV-1 Reverse Transcriptase Inhibitors of 3′,4′-di-O-(S)-camphanoyl-(+)-cis-Khellactone (DCK) Analogs

Contact Info

Product

Resources

About