Discovery of antibacterial biotin carboxylase inhibitors by virtual screening and fragment-based approaches.
As part of our effort to inhibit bacterial fatty acid biosynthesis through the recently validated target biotin carboxylase, we employed a unique combination of two emergent lead discovery strategies. We used both de novo fragment-based drug discovery and virtual screening, which employs 3D shape and electrostatic property similarity searching. We screened a collection of unbiased low-molecular-weight molecules and identified a structurally diverse collection of weak-binding but ligand-efficient fragments as potential building blocks for biotin carboxylase ATP-competitive inhibitors. Through iterative cycles of structure-based drug design relying on successive fragment costructures, we improved the potency of the initial hits by up to 3000-fold while maintaining their ligand-efficiency and desirable physicochemical properties. In one example, hit-expansion efforts resulted in a series of amino-oxazoles with antibacterial activity. These results successfully demonstrate that virtual screening approaches can substantially augment fragment-based screening approaches to identify novel antibacterial agents.
Pfizer, Inc., Michigan Laboratories, Ann Arbor, Michigan 48105, USA. Igor_Mochalkin@yahoo.com
Igor
I
Mochalkin
J Richard
JR
Miller
Lakshmi
L
Narasimhan
Venkataraman
V
Thanabal
Paul
P
Erdman
Philip B
PB
Cox
J V N Vara
JV
Prasad
Sandra
S
Lightle
Michael D
MD
Huband
C Kendall
CK
Stover
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008970:Molecular Weight; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D019731:Carbon-Nitrogen Ligases; C019791:biotin carboxylase