Abstract 2118 Molecular Dynamics Study of a Dozen Secondary Metabolites as Potential Selective Anticholinergic Agents

Selective cholinesterase (ChE) inhibitors are a subject of interest for Alzheimer's Disease research. The present study evaluates secondary metabolites for acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) inhibition, and dual ChE inhibition. Our research group previously performed molecular docking virtual screening against both ChEs. A total of 12 ligands were selected for further analysis via molecular dynamics simulations using GROMACS software on account of their enzyme selectivity in docking. X-ray crystallography-derived atomic structures of AChE and BChE were prepared for the production run using the CHARMM36 forcefield. The lowest energy binding mode from the 12 ligands was chosen as the starting biological conformation, and stream files were generated using the CHARMM General Forcefield (CGenFF) server. Solvent molecules of water and chlorine anions were added to the enzyme-ligand complex. NVT and NPT equilibration steps were carried out with the Berendsen thermostat set for 310.15 K. The Parrinello-Rahman barostat was used for the NPT equilibration step. The molecular dynamics production run was executed for 50 ns. RMSD values for all ligands trended below 0.3 nm after 10 ns of simulation, indicating our enzyme-ligand complexes were well-converged. Short-range Lennard-Jones and Coulombic interactions between ligands and enzymes were calculated and predominantly agreed with the selectivity predictions from the previously performed docking study. Through in silico experimentation, further evidence was found supporting the selective inhibition of ChEs by certain secondary metabolite compounds. The authors would like to thank the support from Research Experience for Undergraduates (REU), STEM-IL, Undergraduate Research Grant (2023), Faculty Research Grants (2022, 2023), the Pittsburgh Supercomputer Center, Carnegie Mellon University, The University of Pittsburgh, and the Chemistry and Biochemistry Department at Southern Connecticut State University.