NIH NIDA DP1 DP1DA058349 (PI: Benjamin P. Brown)
Developing a computational platform for induced-fit and chemogenetic drug design
Project Narrative: Small molecules that selectively activate targeted signaling pathways of the μ-opioid receptor (MOR), such as biased/partial agonists and/or chemogenetic probes, can help to disentangle the mechanisms of analgesia versus dangerous side-effects involved in opioid addiction, as well as potentially act as novel pain management drugs without addictive properties. Here, we will develop computer-aided drug discovery tools that can model large-scale induced-fit conformational changes during drug design and simulate chemogenetics design (receptor-ligand co-design), which we will then apply to identify partial and biased agonists of the MOR and MOR-based DREADDs. In silico molecules and DREADD designs will be experimentally validated and enter hit- to-lead optimization.