Multi-scale Predictions of Drug Resistance Epidemiology Identify Design Principles for Rational Drug Design.

ABSTRACT: Rationally designing drugs that last longer in the face of biological evolution is a critical objective of drug discovery. However, this goal is thwarted by the diversity and stochasticity of evolutionary trajectories that drive uncertainty in the clinic. Although biophysical models can qualitatively predict whether a mutation causes resistance, they cannot quantitatively predict the relative abundance of resistance mutations in patient populations. We present stochastic, first-principle models that are parameterized on a large in vitro dataset and that accurately predict the epidemiological abundance of resistance mutations across multiple leukemia clinical trials. The ability to forecast resistance variants requires an understanding of their underlying mutation biases. Beyond leukemia, a

SUBMITTER: Leighow SM 

PROVIDER: S-EPMC8000225 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature