Computational mapping identifies the binding sites of organic solvents on proteins

Dennis, Sheldon; Körtvélyesi, Tamás; Vajda, Sándor

doi:10.1073/pnas.062398499

Cited by 113 publications

(136 citation statements)

References 25 publications

Supporting

Mentioning

134

Contrasting

Order By: Relevance

“…Examples include nuclear magnetic resonance methods such as SAR (structure-activity relationship) by NMR (11), and the MSCS (multiple solvent crystal structures) approach (12) based on X-ray crystallography. The results of experimental fragment screens confirm that the hot spots of proteins are characterized by their ability to bind a variety of small molecules and that the number of different "probe" molecules observed to bind to a particular site predicts the potential importance of the site and is predictive of overall druggability (11)(12)(13)(14).…”

mentioning

confidence: 61%

“…The hot spots are distinguishable from other regions of the protein surface due to their concave topology combined with a mosaic-like pattern of hydrophobic and polar functionality (13). This combination of properties confers on the hot spots a tendency to bind drug-like organic species possessing some polar functionality decorating a largely hydrophobic scaffold.…”

Section: Discussionmentioning

confidence: 99%

“…Mapping places molecular probes-small organic molecules that vary in size and shape-on a dense grid around the protein, finds favorable positions using empirical free energy functions, clusters the conformations, and ranks the clusters on the basis of the average free energy. The regions that bind several probe clusters are called consensus sites, and the one binding the largest number of probe clusters is considered the main hot spot (13)(14)(15). Based on a variety of proteins using 16 different types of probes, we have shown that the main hot spot in all druggable targets binds at least 16 probe clusters and, together with nearby hot spots, predicts the site that can potentially bind drug-size ligands (13)(14)(15).…”

mentioning

confidence: 99%

“…The regions that bind several probe clusters are called consensus sites, and the one binding the largest number of probe clusters is considered the main hot spot (13)(14)(15). Based on a variety of proteins using 16 different types of probes, we have shown that the main hot spot in all druggable targets binds at least 16 probe clusters and, together with nearby hot spots, predicts the site that can potentially bind drug-size ligands (13)(14)(15). Although solvent mapping shows formal similarity to earlier computational methods (16,17), it correctly shows that small organic molecules bind and cluster only at a few sites on a protein (12).…”

mentioning

confidence: 99%

“…Computational solvent mapping was developed as a virtual analogue of the SAR by NMR and MSCS methods (13). Mapping places molecular probes-small organic molecules that vary in size and shape-on a dense grid around the protein, finds favorable positions using empirical free energy functions, clusters the conformations, and ranks the clusters on the basis of the average free energy.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Structural conservation of druggable hot spots in protein–protein interfaces

Kozakov¹,

Hall²,

Chuang³

et al. 2011

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

Self Cite

223

278

View full text Add to dashboard Cite

Despite the growing number of examples of small-molecule inhibitors that disrupt protein-protein interactions (PPIs), the origin of druggability of such targets is poorly understood. To identify druggable sites in protein-protein interfaces we combine computational solvent mapping, which explores the protein surface using a variety of small "probe" molecules, with a conformer generator to account for side-chain flexibility. Applications to unliganded structures of 15 PPI target proteins show that the druggable sites comprise a cluster of binding hot spots, distinguishable from other regions of the protein due to their concave topology combined with a pattern of hydrophobic and polar functionality. This combination of properties confers on the hot spots a tendency to bind organic species possessing some polar groups decorating largely hydrophobic scaffolds. Thus, druggable sites at PPI are not simply sites that are complementary to particular organic functionality, but rather possess a general tendency to bind organic compounds with a variety of structures, including key side chains of the partner protein. Results also highlight the importance of conformational adaptivity at the binding site to allow the hot spots to expand to accommodate a ligand of drug-like dimensions. The critical components of this adaptivity are largely local, involving primarily low energy side-chain motions within 6 Å of a hot spot. The structural and physicochemical signature of druggable sites at PPI interfaces is sufficiently robust to be detectable from the structure of the unliganded protein, even when substantial conformational adaptation is required for optimal ligand binding.fragment-based drug discovery | ligand binding site | inhibitor design | side-chain adjustment

show abstract

mentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Structural conservation of druggable hot spots in protein–protein interfaces

Kozakov¹,

Hall²,

Chuang³

et al. 2011

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

Self Cite

223

278

View full text Add to dashboard Cite

show abstract

Crystal structure and functional characterization of SF216 from Shigella flexneri

et al. 2017

View full text Add to dashboard Cite

Shigella flexneri is a Gram-negative anaerobic bacterium that causes highly infectious bacterial dysentery in humans. Here, we solved the crystal structure of SF216, a hypothetical protein from the S. flexneri 5a strain M90T, at 1.7 Å resolution. The crystal structure of SF216 represents a homotrimer stabilized by intersubunit interactions and ion-mediated electrostatic interactions. Each subunit consists of three β-strands and five α-helices with the β-β-β-α-α-α-α-α topology. Based on the structural information, we also demonstrate that SF216 shows weak ribonuclease activity by a fluorescence quenching assay. Furthermore, we identify potential druggable pockets (putative hot spots) on the surface of the SF216 structure by computational mapping.

show abstract

Location of Binding Sites on Proteins by the Multiple Solvent Crystal Structure Method

Ringe

Mattos

2006

Fragment‐based Approaches in Drug Discovery

View full text Add to dashboard Cite

IntroductionOne of the greater challenges of structural biology is to characterize proteins in enough detail so that the structures can be used for computational prediction of function, and for the design of compounds that can be used to modulate or to interfere with that function. In general, the function of a protein is associated with its interaction with other molecules, either small molecules or other large biological molecules, such as nucleic acids or proteins. Invariably, the function can be disrupted when that interaction is prevented. A complete industry exists solely for the purpose of finding such disruptors -they are called drugs. The discovery of drugs had been a serendipitous process, in an age when very little was known about the structures of the small molecules or their targets. The process of discovery has become more sophisticated as such structures became available.The success of this process relies on knowing where an interaction site is located on a protein and characterizing the properties of that site. The first step is therefore the location of such a site. The properties of the site can then be used to design a molecule that fits it perfectly in terms of size, shape and chemical properties. One method to obtain such properties is to map a site with chemical probe molecules. Ideally these probe molecules can be connected to form a larger molecule that takes advantage of as many of the potential interaction partners in the site as possible. Finally, when the process of finding and characterizing becomes robust enough, the process can be accomplished computationally.At this moment in time, locating a binding site on a protein without any extraneous information, such as a fortuitously bound ligand in the crystal structure, is only marginally successful. The characterization of a binding site is still very laborious when done experimentally and is not robust when done computationally. Thus, mapping such a site with chemical probes could help characterize the site, the map then being used to design a specific ligand unique for the site. In addition, such a map can provide the data from which computational approaches can be calibrated. One way in which mapping can be achieved is to use a variety of small probe molecules and observe where they bind to the surface of the protein. 67 Fragment-based Approaches in Drug Discovery. Edited

show abstract

Computational mapping identifies the binding sites of organic solvents on proteins

Cited by 113 publications

References 25 publications

Structural conservation of druggable hot spots in protein–protein interfaces

Structural conservation of druggable hot spots in protein–protein interfaces

Crystal structure and functional characterization of SF216 from Shigella flexneri

Location of Binding Sites on Proteins by the Multiple Solvent Crystal Structure Method

Contact Info

Product

Resources

About