Methods and systems for identifying ligand-protein binding sites

A technology for binding sites and proteins, which is applied in biochemical equipment and methods, determination/inspection of microorganisms, and analysis of two-dimensional or three-dimensional molecular structures. Sexuality, not predicting known drug targets, etc.

Active Publication Date: 2017-08-29
KING ABDULLAH UNIV OF SCI & TECH
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Problems solved by technology

However, most of these methods do not predict known drug targets and evaluate their performance (sensitivity analysis). Only Chang et al. [11] and Li et al. [12] reported the true positive predictive rate, but true Positive predictive rates are still relatively low (29% and 49%, respectively)
Furthermore, there is still no emerging high-throughput framework based on structural information, and current methods cannot satisfactorily capture the structural flexibility of drugs that lead to several interactions with different targets that differ in conformation

Method used

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  • Methods and systems for identifying ligand-protein binding sites
  • Methods and systems for identifying ligand-protein binding sites
  • Methods and systems for identifying ligand-protein binding sites

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0132] An Integrated Structure and Systems Based Framework for the Identification of Metabolites and New Targets of Known Drugs

[0133] Build a Probabilistic Pocket Ensemble (PPE)

[0134] Drugs that are inherently promiscuous may bind to different protein pockets with various characteristics, making it difficult to establish a general description of where a drug might bind. To capture the essential binding site features of promiscuous drugs, we established a method for constructing PPE of such drugs (see Methods section for details). The PPE represents a unified collection of individual pockets that may bind to several conformations of the drug. Each position in the PPE can consist of multiple atoms from different residues. The frequency of atoms and residues at each position is recorded and used to construct the maximum probable sequence similarity scoring function. This probability scoring method properly takes into account the fact that a drug can bind to several pocke...

example 2

[0266] Evaluation of PPE and Probability Scoring Function

[0267] To investigate the ability of PPE to retrieve structurally similar drug-binding pockets, we compared the protein pocket bound by 2′-adenosine monophosphate 5′-ribose diphosphate to the predicted binding pockets of the top 10 predicted targets for this compound. Our sequence order-independent alignment overlaps with these 10 predicted targets, and the average normalized RMSD of the drug PPE for this construct is (Alignments contain >4 atoms). In contrast, using sequence order-relative structure alignment, only 2 predicted pockets (within PDB id 2BXP and 3ELM) coincided with the established drug pocket, and the average normalized RMSD was Likewise, using sequence order-relative alignments, the top 10 targets align on average to 9.5 atoms establishing the drug pocket, with an average RMSD of In contrast, with PPE, the average alignment length is 12.4 atoms, and the average RMSD is This result suggests that ...

example 3

[0285] new drug discovery

[0286] For new drugs, our method can be used following the protocol described below.

[0287] 1. Potential binding partners can be identified from a list of commonly observed protein targets (eg, Nature Reviews Drug Discovery 5, 821-834 (October 2006)).

[0288] 2. To test the binding of soluble drugs to recombination to obtain sufficient quantities of the initial list of proteins, we can utilize isothermal titration calorimetry experiments or surface plasmon resonance. For proteins that are not readily available, or drugs that require special solvents (such as DMSO), we can use microthermophoresis or differential scanning fluorescence. Many known protein drug targets are readily available commercially, and many expression plasmids are available in the nonprofit ADDGENE database.

[0289] 3. In order to obtain the binding site of a new drug to one of the above proteins (with sufficiently high interaction strength), we can perform x-ray crystallogr...

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Abstract

The invention provides a novel integrated structure and system-based approach for drug target prediction that enables the large-scale discovery of new targets for existing drugs Novel computer-readable storage media and computer systems are also provided. Methods and systems of the invention use novel sequence order-independent structure alignment, hierarchical clustering, and probabilistic sequence similarity techniques to construct a probabilistic pocket ensemble (PPE) that captures even promiscuous structural features of different binding sites for a drug on known targets. The drug's PPE is combined with an approximation of the drug delivery profile to facilitate large-scale prediction of novel drug- protein interactions with several applications to biological research and drug development.

Description

technical field [0001] The present invention provides a novel method for target prediction of ligands (such as drugs) based on integrated structures and systems, which can discover new targets of existing drugs on a large scale. The present invention also provides novel computer-readable storage media and computer systems. [0002] The method and system of the present invention adopt a novel sequence order-independent structure comparison method, split hierarchical clustering method and probabilistic sequence similarity method to construct a probability pocket set that can even capture the mixed structural characteristics of different binding sites of drugs on known targets (PPE). Combining the PPE of a ligand (such as a drug) with an approximate drug release profile enables large-scale prediction of novel drug-protein interactions, which can be applied in biological research and drug development. [0003] In a cross-validation study, the exemplary method of the present inve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G06F19/16
CPCG16B15/00C12Q2600/158G16B30/00G16B50/00G01N33/6845
Inventor 高欣H·纳维德
Owner KING ABDULLAH UNIV OF SCI & TECH
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