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Profiling MAP kinase cysteines for targeted covalent inhibitor design
Ruibin Liu1, Neha Verma1, Jack A Henderson1
1University of Maryland School of Pharmacy Baltimore MD USA jana.shen@rx.umaryland.edu.
RSC Medicinal Chemistry
|February 28, 2022
Summary
GPU-accelerated constant pH molecular dynamics (CpHMD) identified reactive cysteine sites across all 14 mitogen-activated protein kinases (MAPK). This computational approach aids targeted covalent inhibitor design by predicting druggable sites for drug discovery.
Area of Science:
- Biochemistry
- Computational Chemistry
- Pharmacology
Background:
- Mitogen-activated protein kinases (MAPK) are crucial therapeutic targets, but no MAPK inhibitors have reached the market.
- Targeted covalent inhibitors offer a promising therapeutic strategy, requiring detailed knowledge of reactive amino acid residues.
Purpose of the Study:
- To computationally profile the pKa values and cysteine reactivities of all 14 MAPKs.
- To assist in the rational design of targeted covalent inhibitors against MAPKs.
Main Methods:
- Utilized GPU-accelerated continuous constant pH molecular dynamics (CpHMD) simulations.
- Calculated pKa values and mapped cysteine reactivities across the MAPK family.
- Analyzed kinase conformations (DFG-in/out) to understand reactivity modulation.
Main Results:
- Recapitulated and rationalized known reactive cysteines in JNK and p38α kinases.
- Identified context-dependent reactivity of DFG-1 cysteine in ERK1/2 and MKK7, highlighting the potential of type II inhibitors.
- Prospectively predicted novel druggable cysteine and lysine sites, validated by chemical proteomic data.
Conclusions:
- CpHMD simulations provide a cost-effective, physics-based method for profiling kinase cysteine reactivities.
- This approach complements chemo-proteomic methods for systematic drug discovery targeting MAPKs.
- Computational profiling of reactive sites is essential for advancing targeted covalent inhibitor development.
