4KZ5

Crystal structure of AmpC beta-lactamase in complex with fragment 5 (N-{[3-(2-chlorophenyl)-5-methyl-1,2-oxazol-4-yl]carbonyl}glycine)

Summary for 4KZ5

• Entry DOI: 10.2210/pdb4kz5/pdb
• Related: 4KZ3 4KZ4 4KZ6 4KZ7 4KZ8 4KZ9 4KZA 4KZB
• Descriptor: Beta-lactamase, N-{[3-(2-chlorophenyl)-5-methyl-1,2-oxazol-4-yl]carbonyl}glycine, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: ampc beta-lactamase, class c, hydrolase, cephalosporinase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Escherichia coli
• Cellular location: Periplasm: P00811
• Total number of polymer chains: 2
• Total formula weight: 80145.11

Authors

Eidam, O.,Barelier, S.,Fish, I.,Shoichet, B.K. (deposition date: 2013-05-29, release date: 2014-05-21, Last modification date: 2023-09-20)

Primary citation

Barelier, S.,Eidam, O.,Fish, I.,Hollander, J.,Figaroa, F.,Nachane, R.,Irwin, J.J.,Shoichet, B.K.,Siegal, G.
Increasing chemical space coverage by combining empirical and computational fragment screens.
Acs Chem.Biol., 9:1528-1535, 2014

PubMed Abstract: Most libraries for fragment-based drug discovery are restricted to 1,000-10,000 compounds, but over 500,000 fragments are commercially available and potentially accessible by virtual screening. Whether this larger set would increase chemotype coverage, and whether a computational screen can pragmatically prioritize them, is debated. To investigate this question, a 1281-fragment library was screened by nuclear magnetic resonance (NMR) against AmpC β-lactamase, and hits were confirmed by surface plasmon resonance (SPR). Nine hits with novel chemotypes were confirmed biochemically with KI values from 0.2 to low mM. We also computationally docked 290,000 purchasable fragments with chemotypes unrepresented in the empirical library, finding 10 that had KI values from 0.03 to low mM. Though less novel than those discovered by NMR, the docking-derived fragments filled chemotype holes from the empirical library. Crystal structures of nine of the fragments in complex with AmpC β-lactamase revealed new binding sites and explained the relatively high affinity of the docking-derived fragments. The existence of chemotype holes is likely a general feature of fragment libraries, as calculation suggests that to represent the fragment substructures of even known biogenic molecules would demand a library of minimally over 32,000 fragments. Combining computational and empirical fragment screens enables the discovery of unexpected chemotypes, here by the NMR screen, while capturing chemotypes missing from the empirical library and tailored to the target, with little extra cost in resources.

PubMed: 24807704
DOI: 10.1021/cb5001636

Experimental method

X-RAY DIFFRACTION (1.35 Å)