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Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.

ABSTRACT: The identification of hot spots, i.e., binding regions that contribute substantially to the free energy of ligand binding, is a critical step for structure-based drug design. Here we present the application of two fragment-based methods to the detection of hot spots for DJ-1 and glucocerebrosidase (GCase), targets for the development of therapeutics for Parkinson's and Gaucher's diseases, respectively. While the structures of these two proteins are known, binding information is lacking. In this study we employ the experimental multiple solvent crystal structures (MSCS) method and computational fragment mapping (FTMap) to identify regions suitable for the development of pharmacological chaperones for DJ-1 and GCase. Comparison of data derived via MSCS and FTMap also shows that FTMap, a computational method for the identification of fragment binding hot spots, is an accurate and robust alternative to the performance of expensive and difficult crystallographic experiments.

SUBMITTER: Landon MR

PROVIDER: S-EPMC2889209 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Publications

Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.

Landon Melissa R MR Lieberman Raquel L RL Hoang Quyen Q QQ Ju Shulin S Caaveiro Jose M M JM Orwig Susan D SD Kozakov Dima D Brenke Ryan R Chuang Gwo-Yu GY Beglov Dmitry D Vajda Sandor S Petsko Gregory A GA Ringe Dagmar D

Journal of computer-aided molecular design 20090612 8

The identification of hot spots, i.e., binding regions that contribute substantially to the free energy of ligand binding, is a critical step for structure-based drug design. Here we present the application of two fragment-based methods to the detection of hot spots for DJ-1 and glucocerebrosidase (GCase), targets for the development of therapeutics for Parkinson's and Gaucher's diseases, respectively. While the structures of these two proteins are known, binding information is lacking. In this ...[more]

PMID: 19521672

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Project description:In drug design, chemical groups are sequentially added to improve a weak-binding fragment into a tight-binding lead molecule. Often, the direction to make these additions is unclear, and there are numerous chemical modifications to choose. Lead development can be guided by crystal structures of the fragment-bound protein, but this alone is unable to capture structural changes like closing or opening of the binding site and any side-chain movements. Accounting for adaptation of the site requires a dynamic approach. Here, we use molecular dynamics calculations of small organic solvents with protein-fragment pairs to reveal the nearest "hot spots". These close hot spots show the direction to make appropriate additions and suggest types of chemical modifications that could improve binding affinity. Mixed-solvent molecular dynamics (MixMD) is a cosolvent simulation technique that is well established for finding binding "hot spots" in active sites and allosteric sites of proteins. We simulated 20 fragment-bound and apo forms of key pharmaceutical targets to map out hot spots for potential lead space. Furthermore, we analyzed whether the presence of a fragment facilitates the probes' binding in the lead space, a type of binding cooperativity. To the best of our knowledge, this is the first use of cosolvent MD conducted with bound inhibitors in the simulation. Our work provides a general framework to extract molecular features of binding sites to choose chemical groups for growing lead molecules. Of the 20 systems, 17 systems were well mapped by MixMD. For the three not-mapped systems, two had lead growth out into solution away from the protein, and the third had very small modifications which indicated no nearby hot spots. Therefore, our lack of mapping in three systems was appropriate given the experimental data (true-negative cases). The simulations are run for very short time scales, making this method tractable for use in the pharmaceutical industry.

Dataset Information

Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.

Publications

Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.

Similar Datasets

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