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Reproducing crystal binding modes of ligand functional groups using Site-Identification by Ligand Competitive Saturation (SILCS) simulations.

ABSTRACT: The applicability of a computational method, Site Identification by Ligand Competitive Saturation (SILCS), to identify regions on a protein surface with which different types of functional groups on low-molecular weight inhibitors interact is demonstrated. The method involves molecular dynamics (MD) simulations of a protein in an aqueous solution of chemically diverse small molecules from which probability distributions of fragments types, termed FragMaps, are obtained. In the present application, SILCS simulations are performed with an aqueous solution of 1 M benzene and propane to map the affinity pattern of the protein for aromatic and aliphatic functional groups. In addition, water hydrogen and oxygen atoms serve as probes for hydrogen-bond donor and acceptor affinity, respectively. The method is tested using a set of 7 proteins for which crystal structures of complexes with several high affinity inhibitors are known. Good agreement is obtained between FragMaps and the positions of chemically similar functional groups in inhibitors as observed in the X-ray crystallographic structures. Quantitative capabilities of the SILCS approach are demonstrated by converting FragMaps to free energies, termed Grid Free Energies (GFE), and showing correlation between the GFE values and experimental binding affinities. For proteins for which ligand decoy sets are available, GFE values are shown to typically score the crystal conformation and conformations similar to it more favorable than decoys. Additionally, SILCS is tested for its ability to capture the subtle differences in ligand affinity across homologous proteins, information which may be of utility toward specificity-guided drug design. Taken together, our results show that SILCS can recapitulate the known location of functional groups of bound inhibitors for a number of proteins, suggesting that the method may be of utility for rational drug design.

SUBMITTER: Raman EP

PROVIDER: S-EPMC3090225 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Reproducing crystal binding modes of ligand functional groups using Site-Identification by Ligand Competitive Saturation (SILCS) simulations.

Raman E Prabhu EP Yu Wenbo W Yu Wenbo W Guvench Olgun O Mackerell Alexander D AD

Journal of chemical information and modeling 20110401 4

The applicability of a computational method, Site Identification by Ligand Competitive Saturation (SILCS), to identify regions on a protein surface with which different types of functional groups on low-molecular weight inhibitors interact is demonstrated. The method involves molecular dynamics (MD) simulations of a protein in an aqueous solution of chemically diverse small molecules from which probability distributions of fragments types, termed FragMaps, are obtained. In the present applicatio ...[more]

PMID: 21456594

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Project description:BackgroundFragment-based ligand design is used for the development of novel ligands that target macromolecules, most notably proteins. Central to its success is the identification of fragment binding sites that are spatially adjacent such that fragments occupying those sites may be linked to create drug-like ligands. Current experimental and computational approaches that address this problem typically identify only a limited number of sites as well as use a limited number of fragment types.MethodsThe site-identification by ligand competitive saturation (SILCS) approach is extended to the identification of fragment bindings sites, with the method termed SILCS-Hotspots. The approach involves precomputation of the SILCS FragMaps following which the identification of Hotspots, performed by identifying of all possible fragment binding sites on the full 3D structure of the protein followed by spatial clustering.ResultsThe SILCS-Hotspots approach identifies a large number of sites on the target protein, including many sites not accessible in experimental structures due to low binding affinities and binding sites on the protein interior. The identified sites are shown to recapitulate the location of known drug-like molecules in both allosteric and orthosteric binding sites on seven proteins including the androgen receptor, the CDK2 and Erk5 kinases, PTP1B phosphatase and three GPCRs; the β2-adrenergic, GPR40 fatty-acid binding and M2-muscarinic receptors. Analysis indicates the importance of considering all possible fragment binding sites, and not just those accessible to experimental methods, when identifying novel binding sites and performing ligand design versus just considering the most favorable sites. The approach is shown to identify a larger number of known binding sites of drug-like molecules versus the commonly used FTMap and Fpocket methods.General significanceThe present results indicate the potential utility of the SILCS-Hotspots approach for fragment-based rational design of ligands, including allosteric modulators.

Project description:Drug-induced cardiotoxicity is a potentially lethal and yet one of the most common side effects with the drugs in clinical use. Most of the drug-induced cardiotoxicity is associated with an off-target pharmacological blockade of K+ currents carried out by the cardiac Human-Ether-a-go-go-Related (hERG1) potassium channel. There is a compulsory preclinical stage safety assessment for the hERG1 blockade for all classes of drugs, which adds substantially to the cost of drug development. The availability of a high-resolution cryogenic electron microscopy (cryo-EM) structure for the channel in its open/depolarized state solved in 2017 enabled the application of molecular modeling for rapid assessment of drug blockade by molecular docking and simulation techniques. More importantly, if successful, in silico methods may allow a path to lead-compound salvaging by mapping out key block determinants. Here, we report the blind application of the site identification by the ligand competitive saturation (SILCS) protocol to map out druggable/regulatory hotspots in the hERG1 channel available for blockers and activators. The SILCS simulations use small solutes representative of common functional groups to sample the chemical space for the entire protein and its environment using all-atom simulations. The resulting chemical maps, FragMaps, explicitly account for receptor flexibility, protein-fragment interactions, and fragment desolvation penalty allowing for rapid ranking of potential ligands as blockers or nonblockers of hERG1. To illustrate the power of the approach, SILCS was applied to a test set of 55 blockers with diverse chemical scaffolds and pIC50 values measured under uniform conditions. The original SILCS model was based on the all-atom modeling of the hERG1 channel in an explicit lipid bilayer and was further augmented with a Bayesian-optimization/machine-learning (BML) stage employing an independent literature-derived training set of 163 molecules. BML approach was used to determine weighting factors for the FragMaps contributions to the scoring function. pIC50 predictions from the combined SILCS/BML approach to the 55 blockers showed a Pearson correlation (PC) coefficient of >0.535 relative to the experimental data. SILCS/BML model was shown to yield substantially improved performance as compared to commonly used rigid and flexible molecular docking methods for a well-established cohort of hERG1 blockers, where no correlation with experimental data was recorded. SILCS/BML results also suggest that a proper weighting of protonation states of common blockers present at physiological pH is essential for accurate predictions of blocker potency. The precalculated and optimized SILCS FragMaps can now be used for the rapid screening of small molecules for their cardiotoxic potential as well as for exploring alternative binding pockets in the hERG1 channel with applications to the rational design of activators.

Dataset Information

Reproducing crystal binding modes of ligand functional groups using Site-Identification by Ligand Competitive Saturation (SILCS) simulations.

Publications

Reproducing crystal binding modes of ligand functional groups using Site-Identification by Ligand Competitive Saturation (SILCS) simulations.

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