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Monthly Publication Highlight - Drs. Watts & Lill Published on Purdue College of Pharmacy (https://www.pharmacy.purdue.edu) Monthly Publication Highlight - Drs. Watts & Lill February 21, 2017 - The Purdue College of Pharmacy is pleased to honor and recognize the outstanding research and scholarship generated by our faculty each month. This month we highlight Drs. Val Watts and Markus Lill. Dr. Watts is Associate Head and Professor of the Department of Medicinal Chemistry and Molecular Pharmacology (MCMP), and Dr. Lill is Associate Professor of MCMP. Their recent publication, “Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor”, can be read in Journal of Chemical Information and Modeling (January 26, 2017; doi: 10.1021/acs.jcim.6b00454. PMID: 2806808 ). Research contributors include MCMP graduate students Neha Rana, Jason Conley, and Monica Soto-Velasquez, as well as colleagues at the University of Mississippi, Drs. Francisco León and Stephen Cutler. This paper exemplifies the ongoing collaboration between Drs. Watts’s and Lill’s research group on adenylyl cyclases. Adenylyl cyclase 2 (AC2) is one of the isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important secondary messenger molecule. Up-regulation of AC2 is linked to several cancers. Previously, an isoform-selective and non-competitive inhibitor of AC2, SKF83566, was identified by Dr. Watts’s laboratory in a high throughput screen (Conley et al., 2013). In the current paper, molecular modeling approaches are described to explore the mode of inhibition of AC2 by SKF83566 and to identify the active enantiomer of SKF83566. With a combination of homology modeling, flexible docking, molecular dynamics (MD) simulations, and free energy calculations, an allosteric mechanism was revealed where (S)-SKF83566 binds to an allosteric site near ATP, thereby altering the protein conformation around the ATP binding site, preventing the enzymatic reaction of ATP to cAMP. The predicted binding preference for the (S)-SKF83566 enantiomer and the allosteric mode of action is consistent with experimental data. “This exciting and productive collaboration of our two research groups on adenylyl cyclases demonstrates how very different methods and approaches can be successfully combined to target a significant challenge in drug discovery, designing isoform-selective chemical probes or lead compounds,” Dr. Lill comments. Drs. Watts and Lill are currently using this approach to identify selective inhibitors of adenylyl cyclase type 1 (AC1) as non-opioid analgesics for chronic pain. © Purdue University Page 1 of 2
