Integrating Synthetic, Bioanalytical, and Computational Approaches to Drug Design
With its origins from a casual hallway conversation between Professor Roger Acey and Kensaku Nakayama some years ago, these two began a collaboration focused on examining the development of inhibitors that targeted butyrylcholinesterase (BChE) at a time when researchers were largely focused on inhibiting acetylcholinesterase (AChE) to treat cognitive loss among patients suffering from Alzheimer's disease (AD). Profs. Acey & Nakayama soon realized that simple structural modifications to organophosphorus inhibitors could greatly enhance the selectivity of BChE inhibition over that of AChE. These early observations encouraged their collaboration to search for more effective organophosphorus inhibitors, leading to their initial collaborative publication in 2007.
Soon thereafter, Prof. Eric Sorin was enlisted to complement the synthetic and biochemical methods being employed with computer-based modeling and, more recently, this collaboration expanded to include Prof. Jason Schwans. The Nakayama, Schwans, and Sorin labs recently published their first collaborative article, "Synthesis, biochemical evaluation, and molecular modeling studies of aryl and arylalkyl di-n-butyl phosphates, effective butyrylcholinesterase inhibitors", in Bioorganic & Medicinal Chemistry (2017, 25, 3171-3181), illustrating the sensitivity of inhibitor activity to chemical modification and providing a structural basis for the striking changes in inhibitor potency. The article was co-authored by five CNSM undergraduate and graduate students.
These observations serve as the basis for additional families of derivatives now under investigation, as well as motivating much more time-consuming and computationally intensive studies to better understand the dynamic nature of the BChE-inhibitor complex. In addition, Professor Kevin Sinchak is contributing his expertise via animal studies to evaluate the potential of previous and future compounds of investigation to treat AD-related cognitive loss. This multi-pronged approach represents a fruitful integration of subfields within our Department aimed at the singular goal of identifying new compounds for potential use in mitigating neurodegenerative diseases.
