PROJECT #16907 RESEARCH FOR CANCER
FOLDING PERFORMANCE PROFILE

PROJECT SUMMARY

Recently, cyclic peptides have gained increasing interests due to their potential applications in the “undruggable” target space of intracellular protein-protein interactions that are difficult to target using small molecules. Although the size and complexity of most cyclic peptides often fail to meet Lipinski’s Rule of Five (1) for predicting drug-likeness, there are known examples of natural products such as cyclosporin A (CsA) that can cross cell membrane by passive diffusion. However, its mutant, CsE has one order of magnitude lower permeability, even though it differs only in one backbone methylation. Early studies (2, 3) give insights into studying the conformational behaviors of CsA and CsE from kinetic aspect to understand the siginificant difference. Thus, in this study, we will perform all-atom MD simulations to study the conformational behaviors of CsA and its varivants in solvents and crossing membrane.  We hope with the kinetic information obtained from our MD simulation, we could investigate and rationalize the differences in permeability of CsA and its variants as well as other cyclic peptide families from kinetic aspects.

References:

(1) Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods.

(2) Witek, J., Keller, B. G., Blatter, M., Meissner, A., Wagner, T., & Riniker, S. (2016). Kinetic Models of Cyclosporin A in Polar and Apolar Environments Reveal Multiple Congruent Conformational States. Journal of Chemical Information and Modeling.

(3) Ahlbach, C. L., Lexa, K. W., Bockus, A. T., Chen, V., Crews, P., Jacobson, M. P., & Lokey, R. S. (2015). Beyond cyclosporine A: Conformation-dependent passive membrane permeabilities of cyclic peptide natural products. Future Medicinal Chemistry.

PROJECT INFO

Manager(s): Si Zhang

Institution: Temple University

Project URL: http://voelzlab.org

PROJECT WORK UNIT SUMMARY

Atoms: 6,800

Core: OPENMM_21

Status: Public