P/F Project #: Natural product-based chemical probes for TRPM8 (V. Blair Journigan, Ph.D., Assistant Professor of Medicinal Chemistry, Department of Pharmaceutical Sciences, Marshall University)

Specific Aims.   Dr. Journigan is a new investigator at Marshall University in the Department of Pharmaceutical Sciences. The Journigan lab is focused on the discovery of novel small molecule chemical probes for the transient receptor potential melastatin 8 (TRPM8) ion channel, commonly known as the menthol receptor, to uncover novel therapies for nicotine addiction and neuropathic pain. The project will benefit from Cores A and B. We will first focus on modeling stimuli-dependent structural changes resulting in activation of the channel, to gain a structure-based understanding of conformational rearrangements that may play a role in opening/closing. Subsequent work will focus on docking and molecular dynamics (MD) simulations of TRPM8 agonist and antagonist ligands in our human TRPM8 homology model based on the avian cryo-EM structure (PDB 6BPQ),(1) including our novel antagonist scaffolds, to gain a structure-based understanding of the molecular determinants for ligand recognition. The Journigan lab is interested in elucidating a pharmacophore model for TRPM8 ligands, based on their predicted binding epitopes in the putative orthosteric site. These computational studies will enable structure-based design of novel menthol-based chemotypes. Targets identified in silico will be synthesized by the PI Journigan, and evaluated in binding, calcium flux and whole-cell patch clamp assays in cross-disciplinary collaborations with her laboratory. In the present P/F project, we proposed three specific aims:

Aim 1. To model temperature-, ligand-, and voltage-dependent structural changes responsible for opening and closing of the TRPM8 channel

Aim 2. To determine the molecular basis for small molecule ligand recognition for agonist and antagonist profiles, guided by molecular docking and MD simulations in our hTRPM8 homology model

Aim 3. To design and synthesize high affinity, selective menthol-based TRPM8 chemical probes, via molecular docking and MD simulations, iterative SAR studies, and Target Hunter technology