UCSF

Rational drug design is a multimodal optimization problem where most of the control nodes are at least partially obscured. Fundamentally, rational drug design is predicated on a deep understanding of biological molecular recognition. Arguably, biological molecular recognition is an amalgamation of two principles. Chiefly, biological molecular recognition relies on a so-called metabolic code of logic. This code defines a logic for all the chemical moieties that biological systems use to achieve molecular recognition. At some level, biological interactions are iterations and combinations of only a small set of chemical interactions between a very exclusive set of chemical functional groups. Harnessing this underlying logic to rationally design drugs is the primary investigation of this thesis. This inquiry is supported by another old and well developed theory of biological interactions, that of pre-organization. Pre-organization supposes that biological systems that have evolved specific molecular recognition have done so by paying an energetic cost during folding to pre-organize an energetically unfavorable binding site that relaxes dramatically upon the desired complexation event. One promising approach to tackling this immense problem is by employing computational models of ligand-protein interactions using coarse physical models of the complexation event. The focus of this dissertation is to understand molecular recognition for a clinically relevant and widely generalizable model system, the membrane embedded mu opioid receptor, a 7-pass transmembrane protein receptor that plays a fundamental role in pain perception and analgesia. In this thesis, I employ molecular docking, a computational approach that assesses physical complementarity between a ligand and a protein target to screen humongous chemical space. I then experimentally characterize a number of new to the planet opioid small molecules, and even solve a structure of the most potent compound in complex with the human opiate receptor. In so doing, I not only uncover new to the planet opioid therapeutics, but also learn some fundamental new qualities regarding molecular recognition at the human mu opioid receptor. Also included in this dissertation is a commentary on the state of education in the biomedical enterprise. This PhD experience was unique because it happened amidst a racialized global pandemic and a period of extended social uncertainty and unrest. During this time, student leaders capitalized on the heightened societal focus on social justice. In the final chapter of this dissertation, I share my experiences in this domain and offer some of my personal insights for addressing historical injustices in the biomedical enterprise and making science more representative of our population and more efficacious in solving difficult problems in the domain of human health and wellness.