FTMAP: extended protein mapping with user-selected probe molecules

Ngan, Chi Ho; Bohnuud, Tanggis; Mottarella, Scott E.; Beglov, Dmitri; Villar, Elizabeth A.; Hall, David R.; Kozakov, Dima; Vajda, Sándor

doi:10.1093/nar/gks441

Cited by 139 publications

(135 citation statements)

References 22 publications

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“…Site 4 is also predicted to be druggable when using the solvent-mapping program FTMap (30), as shown in Fig. 8A, again supporting the idea that inhibitors that bind to site 4 will be good drug leads.…”

Section: Comparison Of E Coli and S Aureus Upps Structures And Theirmentioning

confidence: 61%

Antibacterial drug leads targeting isoprenoid biosynthesis

Zhu

Zhang

Sinko³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

163

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With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC) 90 ∼0.25 μg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.drug discovery | in silico high-throughput screening | peptidoglycan | protein structure

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Section: Comparison Of E Coli and S Aureus Upps Structures And Theirmentioning

confidence: 61%

Antibacterial drug leads targeting isoprenoid biosynthesis

Zhu

Zhang

Sinko³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

163

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“…The first kinase cluster representatives were used to predict possible binding pockets using the FTMap web server. 34 Principal Component Analysis (PCA) was performed on the kinase domain (residues 697-1068). PCA of an MD trajectory, also known as essential dynamics, is a technique routinely used to separate large-scale correlated motions in a system from random thermal fluctuations.…”

Section: And Hydrogen Bond and Saltmentioning

confidence: 99%

Exploring a Non-ATP Pocket for Potential Allosteric Modulation of PI3Kα

et al. 2014

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Allosteric modulators offer a novel approach for kinase inhibition because they target less conserved binding sites compared to the active site; thus, higher selectivity may be obtained. PIK-108, a known pan phosphoinositide 3-kinase (PI3K) inhibitor, was recently detected to occupy a non-ATP binding site in the PI3Kα C-lobe. This newly identified pocket is located close to residue 1047, which is frequently mutated in human cancers (H1047R). In order to assess the interactions, stability, and any possible allosteric effects of this inhibitor on PI3Kα, extensive molecular dynamics (MD) simulations in aqueous solution were performed for the wild type (WT) human, WT murine, and H1047R human mutant PI3Kα proteins with PIK-108 placed in both catalytic and non-ATP sites. We verify the existence of the second binding site in the vicinity of the hotspot H1047R PI3Kα mutation through binding site identification and MD simulations. PIK-108 remains stable in both sites in all three variants throughout the course of the simulations. We demonstrate that the pose and interactions of PIK-108 in the catalytic site are similar in the murine WT and human mutant forms, while they are significantly different in the case of human WT PI3Kα protein. PIK-108 binding in the non-ATP pocket also differs significantly among the three variants. Finally, we examine whether the non-ATP binding site is implicated in PI3Kα allostery in terms of its communication with the active site using principal component analysis and perform in vitro experiments to verify our hypotheses.

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“…The third server is FTFlex, which performs repeated mapping calculations while exploring low energy conformers of side chains in the vicinity of hot spots 30 , primarily for opening pockets in protein-protein interfaces that have the potential to bind small ligands 28 . The fourth server is FTMap/param 31 , which can be used to determine whether small molecules selected by the user bind in the hot spot regions predicted by FTMap. Finally, the FTDyn server has been developed to map ensembles of conformationally diverse structures, obtained by Nuclear Magnetic Resonance (NMR) experiments 32 or by molecular dynamics (MD) simulations 21,33 .…”

Section: Introductionmentioning

confidence: 99%

The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins

et al. 2015

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FTMap is a computational mapping server that identifies binding hot spots of macromolecules, i.e., regions of the surface with major contributions to the ligand binding free energy. To use FTMap, users submit a protein, DNA, or RNA structure in PDB format. FTMap samples billions of positions of small organic molecules used as probes and scores the probe poses using a detailed energy expression. Regions that bind clusters of multiple probe types identify the binding hot spots, in good agreement with experimental data. FTMap serves as basis for other servers, namely FTSite to predict ligand binding sites, FTFlex to account for side chain flexibility, FTMap/param to parameterize additional probes, and FTDyn to map ensembles of protein structures. Applications include determining druggability of proteins, identifying ligand moieties that are most important for binding, finding the most bound-like conformation in ensembles of unliganded protein structures, and providing input for fragment based drug design. FTMap is more accurate than classical mapping methods such as GRID and MCSS, and is much faster than the more recent approaches to protein mapping based on mixed molecular dynamics. Using 16 probe molecules, the FTMap server finds the hot spots of an average size protein in less than an hour. Since FTFlex performs mapping for all low energy conformers of side chains in the binding site, its completion time is proportionately longer.

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FTMAP: extended protein mapping with user-selected probe molecules

Cited by 139 publications

References 22 publications

Antibacterial drug leads targeting isoprenoid biosynthesis

Antibacterial drug leads targeting isoprenoid biosynthesis

Exploring a Non-ATP Pocket for Potential Allosteric Modulation of PI3Kα

The FTMap family of web servers for determining and characterizing ligand-binding hot spots of proteins

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