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Are target-family-privileged substructures truly privileged?
Dora M Schnur1, Mark A Hermsmeier, Andrew J Tebben
1Computer Aided Drug Design and Lead Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. dora.schnur@bms.com
Journal of Medicinal Chemistry
|March 17, 2006
Summary
The study challenges the concept of "target-family-privileged substructures" in drug discovery. Analysis reveals many identified fragments are simply drug-like, not selective for specific receptor families like G-protein coupled receptors (GPCRs).
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Drug Discovery
Background:
- Historically, identifying target-family-privileged substructures aided combinatorial library design for G-protein coupled receptors (GPCRs).
- Methods like framework analysis and pharmacophores were used to find these substructures, assuming their frequent occurrence indicated selectivity.
- However, the selectivity of these substructures for their originating target families was rarely verified.
Purpose of the Study:
- To investigate the selectivity of ClassPharmer-generated fragments for various target families.
- To evaluate the substructure composition of a G-protein coupled receptor (GPCR) focused library and a random compound set.
- To critically assess the validity of the target-family-privileged substructure concept in combinatorial chemistry.
Main Methods:
- Utilized ClassPharmer to generate fragments from ligand sets.
- Analyzed the selectivity of these fragments across multiple target families: GPCRs, nuclear hormone receptors, serine proteases, protein kinases, and ligand-gated ion channels.
- Examined substructure composition in a GPCR-focused library and a 10,000-compound random set.
Main Results:
- The study found that fragments previously considered target-family-privileged often lacked selectivity for their specific receptor families.
- Many identified substructures were found to be generally drug-like or attractive to a broad range of receptors.
- This suggests that frequency of occurrence alone is insufficient to label a substructure as target-family-privileged.
Conclusions:
- The concept of target-family-privileged substructures in combinatorial chemistry is challenged by this research.
- Many commonly used fragments may possess general drug-like properties rather than specific target family selectivity.
- Re-evaluation of substructure selection criteria is needed for effective library design.