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When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

ABSTRACT: Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragments, simple structure-based modeling proves far more effective for identifying substitutions that alter the binding mode. Some ligand pairs change binding mode because the added substituent would irreconcilably conflict with the receptor in the original pose, whereas others change because the added substituent enables new, stronger interactions that are available only in a different pose. Scaffolds that can engage their target using alternate poses may enable productive structure-based optimization along multiple divergent pathways.

SUBMITTER: Malhotra S

PROVIDER: S-EPMC5525026 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Malhotra Shipra S Karanicolas John J

Journal of medicinal chemistry 20161216 1

Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragm ...[more]

PMID: 27982595

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Project description:Protein-ligand docking programs can generate a large number of possible binding orientations for each ligand candidate. The challenge is to identify the orientations closest to the native binding mode using a scoring method. Many different scoring functions have been developed for protein-ligand scoring, but their performance on binding mode prediction is often target-dependent. In this study, a statistical approach was employed to provide a confidence measure of scoring performance in finding close to the correct docked ligand orientations. It exploits the fact that the scores provided by an adequately performing scoring function generally improve as the ligand binding modes get closer to the correct native orientation. For such cases, the correlation coefficient of scores versus distances is expected to be highest when the most native-like orientation is used as a reference. This correlation coefficient, called the correlation-based score (CBScore), was used as an indicator of how far the docked pose was from the native orientation. The correlation between the original scores and CBScores as well as the range of CBScores were found to be good measures of scoring performance. They were combined into a single quantity, called the scoring confidence index. High values of the scoring confidence index were indicative of pronounced and relatively smooth binding energy landscapes with easily discernable global minima, resulting in reliable binding mode predictions. Low values of this index reflected rugged energy landscapes making the prediction of the correct binding mode very difficult and often unreliable. The diagnostic ability of the scoring confidence index was tested on a non-redundant set of 50 protein-ligand complexes scored with three commonly employed scoring functions: AffiScore, DrugScore and X-Score. Binding mode predictions were found to be three times more reliable for complexes with scoring confidence indices in the upper half than for cases with values in the lower half of the resulting range of 0-1.6. This new confidence measure of scoring performance is expected to be a valuable tool for virtual screening applications.

Dataset Information

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Publications

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

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