Structure-Based Drug Design: Docking and Scoring

Kroemer, Romano T.

doi:10.2174/138920307781369382

Cited by 282 publications

(75 citation statements)

References 113 publications

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“…Because none of the presently available dockers are capable of performing well in overcoming the scoring and rank-ordering issues, researchers apply consensus docking and scoring strategies to improve the enrichment of in silico screens 34 . In the present study, we performed docking of the GlideXP-1400 molecule set using two additional well-known dockers commercially available to the scientific community: Surflex and FlexX.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Small Molecule Inhibitors to Krüppel-like Factor 10 (KLF10): Implications for Modulation of T Regulatory Cell Differentiation

et al. 2015

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The Krüppel-like family of transcription factors (KLFs) constitute a subfamily of C2H2-type zinc finger proteins with distinct cell-type expression patterns and regulate functional aspects of cell growth and differentiation, activation, or development. KLF10 has been previously shown to critically regulate the acquisition of CD4+CD25+ T regulatory cell differentiation and function, an effect important to the maintenance of self-tolerance, immune suppression, and tumor immunosurveillance. To date, there are no selective pharmacological inhibitors to KLF10. Herein, we report on the discovery of first-in-class small molecule compounds that inhibit the KLF10-DNA interaction interface using computer-aided drug design (CADD) screens of chemical libraries. Interrogation of a ‘druggable’ pocket in the 2nd zinc-finger of KLF10 revealed three small molecules, #48, #48-15, and #15-09, with similar scaffolds and binding patterns. Each of these small molecules inhibited KLF10-DNA binding and transcriptional activity, conversion of CD4+CD25− T cells to CD4+CD25+ T regulatory cells, and KLF10 target gene expression. Taken together, these findings support the feasibility of using CADD with functional assays to identify small molecules that target members of the KLF subfamily of transcription factors to regulate biological functions in health and disease. We hope these novel compounds will serve as useful mechanistic probes for KLF10-mediated effects and T regulatory cell biology.

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Section: Discussionmentioning

confidence: 99%

Discovery of Small Molecule Inhibitors to Krüppel-like Factor 10 (KLF10): Implications for Modulation of T Regulatory Cell Differentiation

et al. 2015

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“…Virtual screening [17] of compounds using crystal structures [18, 19] as receptors by docking and scoring is one of the most commonly used methods to identify hits and subsequently, lead compounds especially for drug targets such as HIV-1 protease. In the current study, crystal structure of MDR769 HIV-1 protease, with expanded active site cavity and wide-open flaps, was used as a receptor to perform virtual screening of extended LPV analogs.…”

Section: Discussionmentioning

confidence: 99%

P1 and P1′ para-fluoro phenyl groups show enhanced binding and favorable predicted pharmacological properties: Structure-based virtual screening of extended lopinavir analogs against multi-drug resistant HIV-1 protease

Yedidi

Liu

Kovari

et al. 2014

Journal of Molecular Graphics and Modelling

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Crystal structure of multidrug-resistant (MDR) clinical isolate 769, human immunodeficiency virus type-1 (HIV-1) protease in complex with lopinavir (LPV) (PDB ID: 1RV7) showed altered binding orientation of LPV in the expanded active site cavity, causing loss of contacts and decrease in potency. In the current study, with a goal to restore the lost contacts, three libraries of LPV analogs containing extended P1 and/or P1' phenyl groups were designed and docked into the expanded active site cavity of the MDR769 HIV-1 protease. The compounds were then ranked based on three criteria: binding affinity, overall binding profile and predicted pharmacological properties. Among the twelve proposed extensions in different combinations, compound 14 (consists of para-fluoro phenyl group as both P1 and P1' moieties) was identified as a lead with improved binding profile, binding affinity against the MDR protease and favorable predicted pharmacological properties comparable to those of LPV. The binding affinity of 14 against wild type (NL4-3) HIV-1 protease was comparable to that of LPV and was better than LPV against an ensemble of MDR HIV-1 protease variants. Thus, 14 shows enhanced binding affinity by restoring lost contacts in the expanded active site cavity of MDR769 HIV-1 protease variants suggesting that it may have higher potency compared to that of LPV and hence should be further synthesized and evaluated against NL4-3 as well as MDR variants of HIV-1.

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“…One notable important area of application is structureaided drug design. Developments in structure-based virtual screening have been reviewed, for example, by McInnes (2007); ligand docking methods and scoring functions have been specifically covered by others (Krömer 2007;Rajamani & Good 2007). Applications of ligand docking in drug design and the current developments of inclusion of protein flexibility have been described by Cavasotto & Orry (2007) and Joseph-McCarthy et al (2007).…”

Section: Discussionmentioning

confidence: 99%

Biomolecular simulation and modelling: status, progress and prospects

Kamp

Shaw

Woods

et al. 2008

J. R. Soc. Interface.

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Molecular simulation is increasingly demonstrating its practical value in the investigation of biological systems. Computational modelling of biomolecular systems is an exciting and rapidly developing area, which is expanding significantly in scope. A range of simulation methods has been developed that can be applied to study a wide variety of problems in structural biology and at the interfaces between physics, chemistry and biology. Here, we give an overview of methods and some recent developments in atomistic biomolecular simulation. Some recent applications and theoretical developments are highlighted.

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Structure-Based Drug Design: Docking and Scoring

Cited by 282 publications

References 113 publications

Discovery of Small Molecule Inhibitors to Krüppel-like Factor 10 (KLF10): Implications for Modulation of T Regulatory Cell Differentiation

Discovery of Small Molecule Inhibitors to Krüppel-like Factor 10 (KLF10): Implications for Modulation of T Regulatory Cell Differentiation

P1 and P1′ para-fluoro phenyl groups show enhanced binding and favorable predicted pharmacological properties: Structure-based virtual screening of extended lopinavir analogs against multi-drug resistant HIV-1 protease

Biomolecular simulation and modelling: status, progress and prospects

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