Drug Discovery Methods Development and Applications Using Molecular Dynamics Simulations

Development of computational methods for modeling and simulating binding of drugs to their targets for drug discovery. Bridging the gap between the molecular and organoid scales by designing simulation methods for elucidating the molecular mechanism of protein-protein interactions.

Research Outline

Research plan

Peptides as drug candidates
・Efficient sampling of binding/unbinding of protein-peptide (currently computationally difficult)
・Affinity-based screening of drug candidates using free-energy calculations and amino-acid mutations
MD simulation-based personalized medicine
・Identify the structural basis for variation in drug efficacy due to genomic variation among patients
・Design drugs that overcome drug-resistant mutations
Molecular-level description of protein-protein interactions (PPI)
・Identify the crucial elements of PPIs
・Develop multi-scale models for simulating dynamics of protein-protein complexes

Past research and preparation state

•Large-scale simulations of protein-inhibitor binding¹

•Parameter tuning for obtaining a converged free-energy landscape and introduction of parameter setting protocol²

•Effect of inhibitor size and flexibility on the binding mechanism¹

Determination of the correct binding pose of protein-protein complexes^3,4
Coarse-grained model for sampling large conformational changes in proteins^5,6

References

1. Shinobu, A., Re, S., and Sugita, Y. (2022) bioRxiv.
2. Shinobu, A., Re, S., & Sugita, Y. (2022) Front. Mol. Biosci. 9.
3. Shinobu, A., Takemura, K., Matubayasi, N., & Kitao, A. (2018) J. Chem. Phys. 149(19), 195101.
4. Terayama, K.*, Shinobu, A.*, Tsuda, K., Takemura, K., & Kitao, A. (2019) J. Chem. Phys. 151(21), 215104. (*eq’ contribution)
5. Shinobu, A., Kobayashi, C., Matsunaga, Y., & Sugita, Y. (2019) Biophys. physicobiology 16, 310-321.
6. Shinobu, A., Kobayashi, C., Matsunaga, Y., & Sugita, Y. (2021) J. Chem. Inf. Model. 61(5), 2427-2443.