VENUE: Our meetings this year are at the CABM (Center for Advanced Biotechnology and Medicine) on the Rutgers Busch Campus, 679 Hoes Lane West, Piscataway NJ 08854
The meeting is in Room 010, which is located near the main entrance of CABM. Parking is available in the lot across the street from the CABM building. Dinner will be served in the meeting room.
This meeting is sponsored by Bruker BioSpin
“Protein Dynamics and Biophysical Data Driving Drug Design of Staphylococcus aureus DHFR Inhibitors”
CCIE-Structural Biology & Biophysics, Pfizer Global R&D, Groton, CT
“Recent advances in NMR spectroscopy of encapsulated proteins & nucleic acids dissolved in low viscosity fluids”
Prof. Josh Wand,
Johnson Research Foundation and Department of Biochemistry & Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia
- 6:00 pm Dinner
7:00 pm Seminar
CABM (Center for Advanced Biotechnology and Medicine)
on the Rutgers Busch Campus,
679 Hoes Lane West, Piscataway NJ 08854
Dinner cost: $15 (no charge for students / postdoc / retired / unemployed).
No charge for seminar only.
Extra Door Prizes!
(2 door prizes for # of attendees < 20, 3 door prizes for # of attendees > 20)
DHFR is a classic chemotherapeutic and antibacterial target which has been the subject of numerous structural, protein dynamic and mechanistic studies for over 20 years. A clinically relevant drug resistant mutant, S1 of the Staphylococcus aureus (Sa) ortholog of DHFR has been identified and DHFR inhibitors such as Trimethoprim are about 100-1000 fold less potent against it compared to the wild-type. A loss of enthalpy of interaction between compounds and S1 mutant is detected by isothermal calorimetry. The source of these potency differences are not clearly evident based solely on the low energy static WT and S1 X-ray structures. To address this issue, biophysical methods including NMR solution dynamic studies, in conjunction with thermodynamic, kinetic, computational and structural information are being employed to understand potency differences for both in vitro and whole cell MIC activity studies. Protein dynamics observed by NMR clearly show differences in the binding pockets of WT and S1 proteins as binary and ternary complexes with the cofactor NADPH and Trimethoprim. These differences are not observed in static X-ray structures. Differences observed in us-ms range using relaxation dispersion experiments point to important residues involved in the binding of inhibitor in the substrate binding pocket. Kinetics of binding determined by SPR indicate that the reduction in binding affinities arise from faster off rates and they show correlation to whole cell MICs.
In this presentation, the use of biophysical data to generate hypotheses and to guide chemical design for S1 mutant inhibitors will be highlighted.