Ensemble Approaches Yield New Scaffolds and New Binding Sites . Heather A. Carlson Department of Medicinal Chemistry College of Pharmacy University of Michigan Ann Arbor, Michigan 48109-1065. Binding Sites have Dual Characteristics. Blue regions are rigid and red regions are flexible
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Ensemble Approaches YieldNew Scaffolds andNew Binding Sites
Heather A. Carlson
Department of Medicinal Chemistry
College of Pharmacy
University of Michigan
Ann Arbor, Michigan 48109-1065
Binding Sites have Dual Characteristics
Freire. Proc. Natl. Acad. Sci. USA1996, 96, 10118-10122.
Collection of Conformational States
Carlson and McCammon. Mol. Pharmacol. 2000, 57, 213-218.
Original HIV-1 Integrase Studies: Carlson et al. J. Phys. Chem. A1999, 103, 10213-10219.
Carlson et al. J. Med. Chem.2000, 43, 2100-2114.
First HIV-1 Protease Study: Meagher and Carlson. J. Am. Chem. Soc. 2004, 126, 13276-13281.
Consensus Maps Out S1 and S2 Pockets
More Flexibility = Better Performance!
1 ns 4 of 6 sites
3 ns 4 of 6 sites
89 unique, diverse inhibitors
Percent Active Compounds
Percent Inactive Compounds
85 unique, highly diverse, medicinal compounds
Meagher and Carlson. J. Am. Chem. Soc. 2004, 126, 13276-13281.
Fragment-based discovery of inhibitors of HIV-1 protease with a possible new mode of inhibition
Damm et al. Biopolymers, ASAP.
Figure adapted from Hornak and Simmerling. Drug Discov Today2007, 12, 132-138.
7 pharmacophore elements
R2 = 0.9967
compound 2 ●
Pepstatin A □
0.1 1 10 100
Log [Inhibitor] in μM
Compound 2 inhibits HIV-1p IC50 = 18 μM
(no optimization whatsoever)
Collaboration with Jason E. Gestwicki, UMich Life Sciences Institute
1H-15N HSQC Spectra from Reiko Ishima (Pitt)
An unusual crystal structure shows an inorganic ligand with some contacts to the eye
1ZTZ (Cobalt metallacarboraneligands)
Cígler et al. PNAS 2005, 102, 15394-15399.
Note a substrate mimic is bound with two metalo compounds per dimer, and…
the presence of the ligands warps the flap tips outward
The presence of the ligands also creates unusual inter-locking contacts between multiple copies of the protease.
Inhibitors of p53-MDM2
Kussie et al, Science, 1996, 274, 948-953.
6-site MPS model based on snapshots from a 2-ns MD
Bowman et al. J. Am. Chem. Soc.2007, 129, 12809-12814.
Zhong and Carlson. Proteins2005, 58, 222-234
4 of 23 Tested Compounds were Inhibitors
Ki = 0.11 µM Ki = 0.29 µM
Collaboration with Shaomeng Wang, UMich Medical School
Ki = 9.9 µM Ki = 37 µM
GLIDE Flexible Docking
Pushing the Flexible Core of MDM2
Summary of MPS Method
Man-Un “Peter” Ung
Prof. Jason E. Gestwicki
Prof. Reiko Ishima
Dr. Zaneta Nikolovska-Coleska
Prof. Shaomeng Wang