Docking for fragment inhibitors of AmpC β-lactamase

Abstract

Fragment screens for new ligands have had wide success, notwithstanding their constraint to libraries of 1,000 -10,000 molecules. Larger libraries would be addressable were molecular docking reliable for fragment screens, but this has not been widely accepted. To investigate docking's ability to prioritize fragments, a library of >137,000 such molecules were docked against the structure of ␤-lactamase. Forty-eight fragments highly ranked by docking were acquired and tested; 23 had Ki values ranging from 0.7 to 9.2 mM. X-ray crystal structures of the enzyme-bound complexes were determined for 8 of the fragments. For 4, the correspondence between the predicted and experimental structures was high (RMSD between 1.2 and 1.4 Å), whereas for another 2, the fidelity was lower but retained most key interactions (RMSD 2.4 -2.6 Å). Two of the 8 fragments adopted very different poses in the active site owing to enzyme conformational changes. The 48% hit rate of the fragment docking compares very favorably with ''lead-like'' docking and high-throughput screening against the same enzyme. To understand this, we investigated the occurrence of the fragment scaffolds among larger, lead-like molecules. Approximately 1% of commercially available fragments contain these inhibitors whereas only 10 ؊7 % of lead-like molecules do. This suggests that many more chemotypes and combinations of chemotypes are present among fragments than are available among lead-like molecules, contributing to the higher hit rates. The ability of docking to prioritize these fragments suggests that the technique can be used to exploit the better chemotype coverage that exists at the fragment level.crystallography ͉ drug design ͉ hit rates ͉ chemical space

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

“…In themselves, these inhibitors hold promise as leads to overcome a pervasive and growing threat to public health. More generally, whereas fragments are widely used to nucleate early discovery (13)(14)(15)(16)(17)(18)(19)(20)(21)(22), this study suggests that they also may be used to guide late-stage optimization into chemotypes and geometries that would be hard to systematically sample by other methods.…”

“…Whereas fragments have been used previously for new chemotype discovery (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) and merging, their use in late stage optimization has remained largely unexplored. Of course nothing prevented this, and indeed such an idea is implicit in the fragment approach and anticipated by computational design methods like LUDI, HOOK, GrowMol, and MCSS (36)(37)(38)(39).…”

“…Fragments can optimally explore receptor pockets (13)(14)(15)(16)(17)(18) and better cover chemical space (19)(20)(21)(22), and we wondered if they could guide a late-stage optimization that had thus far floundered. In a previous fragment-based docking screen against AmpC (22) and in a defragmentation study of a known AmpC inhibitor (23), crystal structures of three anionic fragments were determined: a thiophene carboxylic acid (F1), a benzoic acid (F2), and an aryl tetrazole (F3), all of which bind in the same distal region of the active site where the aryl carboxylate of compound 2 was placed ( Fig. 1 A, B, and D).…”

Integração das técnicas de triagem virtual e triagem biológica automatizada em alta escala: oportunidades e desafios em P&D de fármacos

“…Apesar das bases de dados de fragmentos serem relativamente pequenas, contando com alguns milhares de compostos, a diversidade estrutural que pode ser explorada no processo de planejamento molecular é significativa. 24,25 A otimização de fragmentos, sejam estes obtidos por triagens experimentais ou computacionais, está diretamente associada à biologia estrutural. O modo de ligação do fragmento na cavidade apropriada do alvo biológico é utilizado como padrão de reconhecimento molecular para a aplicação de métodos de planejamento de fármacos baseado em fragmentos (FBDD -fragment-based drug design).…”

“…Diversos exemplos de sucesso da aplicação da SBVS são descritos na literatura, demonstrando sua versatilidade, alto desempenho e grande utilidade em programas de descoberta fármacos. 12,25,45,[71][72][73] É interessante observar a rica variedade de classes químicas identificadas para uma igualmente abastada diversidade de alvos biológicos.…”