KSEF R&D Excellence: Microscopic and Phenomenological Binding of Nicotinic Acetylcholine Receptors with Ligands

Nicotinic acetylcholine receptors (nAChRs) are important drug targets. It is well-recognized that structure-based drug design is the most powerful approach for drug discovery and design. However, structure-based drug design based on high-performance computing still is a novel area for nAChR/nicotine-related drug discovery and design efforts because of the fact that nAChRs binding with their ligands (agonists and antagonists) have not been well-understood yet. To truly understand the binding of a nAChR with a ligand, a reliable computational protocol is necessary to accurately predict both the microscopic binding free energies of a receptor with all possible molecular species of a given ligand and the phenomenological binding affinity. We propose to develop and test a new computational protocol for modeling nAChR-ligand binding through a combined use a variety of state-of-the-art computational techniques, including our recently developed fully polarizable continuum model (FPCM). For this purpose, we will first focus on two especially important nAChR subtypes, i.e. a4~2 and a7, binding with representative ligands. The development and test of this new computational protocol will include the following three specific aims/steps: (1) to build reliable 3D structures of the nAChRs by performing homology modeling and molecular dynamics (MD) simulations; (2) to determine detailed microscopic binding structures and free energies of representative ligands with the nAChRs by performing molecular docking and MD simulations, accounting for various possible molecular species of a ligand in both solution and receptor binding site; and (3) to accurately predict the phenomenological nAChR-ligand binding affinities by a combined use of a variety of methods, including FPCM-based first-principles electronic structure calculations. Comparison of the calculated results with available experimental data will clearly reveal how good the computational protocol is. Accomplishment of this proposed project will provide a solid structural basis and a reliable computational protocol for future structure-based drug design related to nAChR/nicotine.