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 Dr. Gregory Hockerman, Associate Head and Professor, Department of Medicinal Chemistry and Molecular Pharmacology. Dr. Hockerman’s recent publication, “Molecular Determinants of the Differential Modulation of Cav1.2 and Cav1.3 by Nifedipine and FPL 64176”, can be read in Molecular Pharmacology (September 2018; DOI: 10.1124/mol.118.112441). The study conducted was in collaboration with Graduate students, Shiqi Tang, Kyle Harvey and Emily Rantz; Research Technician, Amy Salyer; PharmD Student, Tingjiao Li and MCMP Faculty Member, Dr. Markus Lill.
Cav1.2 and Cav1.3 are very closely related Ca2+ channels that play very different roles in the body. Cav1.2 is predominant in the cardiovascular system, while Cav1.3 is found mainly in the brain, and in endocrine cells. Drugs that block Cav1.2 are used to treat cardiovascular disease, but most don’t discriminate very well between Cav1.2 and Cav1.3 . We found that nifedipine blocks Cav1.2 more potently than Cav1.3 , with an ~13-fold difference. We identified 2 non-conserved amino acid residues that largely account for this difference. Since no high-resolution structure of Cav1.2 of 1.3 is available, we created a model for each based on the high resolution structure of Cav1.1, another related Ca2+ channel. Our results show that one of the key amino acid residues likely controls access to the drug binding pocket, while the other likely controls mobility of a short helix within the binding pocket via a hydrogen bond.
“Selective inhibition of Cav1.3 is a very promising approach for the treatment of neurodegenerative diseases,” said Dr. Hockerman. “Our results may be useful for the design of Cav1.3 -selective small inhibitors, but that this will be very challenging if the initial screen is for inhibition of channel activity. My lab is currently collaborating with the laboratory of Dr. Casey Krusemark on a strategy to develop selective inhibitors using extracellular toxin binding domains of ion channels as targets to screen DNA-encoded macrocyclic peptide libraries.”