An understanding of optimal drug-target interactions can be highly useful in the design of targeted therapy drugs that effectively recognize and bind rapidly-mutating targets. Charge optimization is a previously-published computational technique that determines the hypothetical, most energetically favorable charge distribution on a molecule to maximize affinity to a given binding partner. In the past, this method has generally been applied to static models. In contrast, a dynamic model, which takes into account fluctuating conformations of drug--protein systems as a function of time, may provide more realistic or comprehensive insights. This project applies charge optimization to snapshots extracted from molecular dynamics simulations, using the Chronic Myeloid Leukemia (CML) drug imatinib and its target, the Abl kinase domain of Bcr-Abl kinase, as a model system. This project aims to determine the extent of impact that structural dynamics have on optimal charge distributions and the degree to which individual drug moieties contribute to overall electrostatic binding free energies for both wild-type and clinically-relevant mutated systems. Additionally, analysis on dynamic models may predict correlation between such impacts and conformational flexibility. The results of this project can guide the future design of CML drugs that efficiently bind to and inhibit the activity of the rapidly-mutating Bcr-Abl kinase in vivo, through comparisons of the optimal drug charge distributions for wild-type and mutated dynamic systems. Additionally, this project illustrates the dependence of optimal electrostatic interactions on conformational dynamics, which has broader implications on the selection of methods used to characterize and maximize drug-target affinity in various systems.

Optimizing electrostatic interactions within dynamic systems: Application to the Imatinib–Abl kinase system

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.