Learning About Allosteric Drugs and Ways to Design Them
Zhen Wah Tan1, Wei-Ven Tee1, Igor N Berezovsky2
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01, Matrix 138671, Singapore.
Journal of Molecular Biology
|June 23, 2022
Summary
Allosteric drugs offer a new frontier for precision medicine, targeting previously undruggable proteins. This study outlines universal allosteric modes and computational methods for designing novel allosteric drugs.
Area of Science:
- Drug Discovery
- Structural Biology
- Pharmacology
Background:
- Precision medicine demands novel drugs targeting complex diseases.
- Allosteric drugs offer a promising avenue for addressing undruggable targets.
- Current understanding of allosteric drug design is limited.
Purpose of the Study:
- To generalize allosteric modes of action applicable across diverse protein targets.
- To introduce methods for identifying allosteric sites and developing effector-leads.
- To propose a computational protocol for rational allosteric drug design.
Main Methods:
- Generalization of allosteric modes from GPCRs and kinases.
- Application of Allosteric Signalling and Probing Fingerprints.
- Fragment-based design and site-ligand mutual adjustment.
- Development of a generic computational protocol for allosteric effector design.
Main Results:
- Established universal allosteric modes of action.
- Identified potential allosteric sites and effector-leads using fingerprinting methods.
- Characterized distinct features of allosteric ligands, highlighting their versatility.
- Demonstrated the potential for allosteric tuning of biologics.
Conclusions:
- Allosteric drugs present significant advantages for personalized medicine.
- Rational design strategies involving latent sites and fragment-based approaches are crucial.
- A generic computational protocol enables the design of allosteric effectors for precise protein function control.
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