Computational study of butyrylcholinesterase inhibition by dialkyl phenyl phosphate derivatives.

POSTER

Abstract

Acetylcholine (ACh) is a neurotransmitter that allows for communication between nerve and muscle cells. While acetylcholinesterase (AChE) is the primary enzyme responsible for the breakdown of ACh to regulate intercellular communication, butyrylcholinesterase (BChE), an AChE-like scavenger enzyme, also breaks down both ACh and larger choline derivatives. In persons suffering from Alzheimer's disease (AD), BChE activity has been found to gradually increase over time and increased BChE activity is believed to significantly decrease synaptic ACh levels, thereby disrupting intercellular communication. It is therefore of interest to explore BChE-specific inhibitors as potential pharmaceutical approaches to the treatment of AD. Dialkyl phenyl phosphate (DAPP) derivatives are organophosphates that mimic the ester moeity of ACh. As such, DAPP derivatives are expected to interact with the BChE binding pocket in a manner similar to that of natural physiological substrates. This study employs massive flexible-inhibitor docking calculations to predict the relative binding affinity between the enzyme and a number of DAPP derivatives, as well as the optimal binding orientation of each DAPP derivative within the BChE active site. Our results reproduce experimental trends in binding affinity and indicate that DAPP derivatives with substitutions at the ortho- and meta- positions of the phenyl ring will show increased inhibitory strength, while para- substitutions will generally be detrimental due to steric clash with active site residues. These findings provide insight into the structural preference of BChE for specific DAPP derivatives and provide a framework for future inhibitor design and testing.

Authors

  • Walter Alvarado

    Cal State Univ- Long Beach

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced

  • Chi-Yu Hu

    University of California - Berkeley, National Institute for Materials Science, Caifornia State University, Long Beach, University of Michigan, Stockholm University, California State University, Long Beach, Utrecht University, Carl von Ossietzky University of Oldenburg, Germany, Hartnell Community College, Department of Physics, Stockholm University, GRAPPA, University of Amsterdam, Paul Scherrer Institute, Switzerland, California State University, Fresno, California State University Long Beach, Cal State Univ- Long Beach, University of Nevada, Reno, University of Rogensberg, Germany, Tribhuvan University, Nepal, University of Victoria and Perimeter Institute for Theoretical Physics, Institute of Physics, Jagiellonian University, Helmholtz Institute Mainz, Johannes Gutenberg University, Physics Department of the University of Nevada, Reno, Universita del Sannio, Cal Tech, California State University, Los Angeles, Univ of California - San Diego, UC Berkeley, Lawrence Livermore National Laboratory, Department of Physics & Astronomy, University of California, Irvine 92617, Department of Chemistry and of Physics & Astronomy, University of California, Irvine 92617, SLAC National Laboratory, Humboldt State University, Physics Department, University of Nevada, Reno, Univ of California - Merced