Professor of Biochemistry and Biophysics
(PhD – Harvard University)
X-ray Structures of Phosphodiesterases and Structure-based drug design
Our research focuses on the structure and function of medically important proteins, and structure-based design of inhibitors for treatment of human diseases. The current topics include enzymatic and structural characterization of cyclic nucleotide phosphodiesterases (PDEs), structure-based design of PDE selective inhibitors, and discovery of novel metallo-β-lactamase (MBL) inhibitors to fight against superbugs.
Cyclic nucleotide phosphodiesterase (PDE) hydrolyzes adenosine or guanosine 3′,5′-cyclic phophate (cAMP or cGMP) to 5′-AMP and 5’-GMP. Selective PDE inhibitors towards a certain family of PDEs have been widely studied as therapeutic agents for treatment of various human diseases. An example is the PDE5 inhibitor VIAGRA that is a prescription drug for the treatment of male erectile dysfunction. Our group has solved >30 crystal structures of several PDE families and recently discovered high selective inhibitors of PDE4, PDE5, and PDE9 (Figure 1).
Fig. 1. Binding of a novel inhibitor (green sticks) to the PDE9 active site.
Superbugs are bacteria resistant to most current antibiotics. While the multidrug resistance may be achieved via several mechanisms such as prevention of drug permeation and mutation of drug targeted proteins, identification of a novel enzyme in 2009, called New Delhi metallo-b-lactamase (NDM-1) that decomposes almost all the b-lactam antibiotics and is spreading worldwide, attracts a great attention. To fight the multidrug resistance of pathogens, we are performing structure-based design of NDM-1 inhibitors and obtained some potent inhibitors against NDM-1 and other MBLs.n
Lab Rooms: 3100D-F Genetic Medicine
Lab Phone: 919-966-7489