Transplant-insert-constrain-relax-assemble (TICRA): protein-ligand complex structure modeling and application to
Siavash Meshkat1, Anthony E Klon, Jinming Zou
1Ansaris, Four Valley Square, 512 Township Line Rd, Blue Bell, Pennsylvania 19422, United States. smeshkat@Locuspharma.com
Journal of Chemical Information and Modeling
|December 2, 2010
Summary
We developed TICRA (transplant-insert-constrain-relax-assemble), a novel method for predicting protein-ligand complex structures. This approach aids structure-based drug design when target information is limited.
Area of Science:
- Computational biology
- Structural biology
- Drug discovery
Background:
- Accurate protein-ligand complex structures are crucial for structure-based drug design.
- Limited structural information for target proteins and unknown binding modes pose challenges.
- Existing methods may struggle with novel protein-ligand interactions.
Purpose of the Study:
- To introduce and validate the TICRA method for modeling unknown protein-ligand complexes.
- To assess TICRA's efficacy using protein kinase-inhibitor complexes as examples.
- To demonstrate TICRA's utility in structure-based drug design with limited data.
Main Methods:
- The TICRA (transplant-insert-constrain-relax-assemble) method was developed.
- Utilized X-ray crystal structures of homologous proteins and active ligands.
- Applied TICRA to model p38 and Lck kinase-inhibitor complexes.
Main Results:
- TICRA successfully modeled protein kinase-inhibitor complexes.
- Achieved backbone root-mean-square deviation (rmsd) < 0.75 Å for kinase domains compared to crystal structures.
- Further refinement improved rmsd to < 0.5 Å for p38 and Lck complexes.
Conclusions:
- TICRA is a valuable tool for modeling protein-ligand complexes.
- The method is effective even with limited structural information.
- TICRA facilitates structure-based drug design for challenging targets.
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