6Y6Z

Structure of Pseudomonas aeruginosa Penicillin-Binding Protein 3 (PBP3) in complex with Compound 1

Summary for 6Y6Z

• Entry DOI: 10.2210/pdb6y6z/pdb
• Descriptor: Peptidoglycan D,D-transpeptidase FtsI, ~{tert}-butyl ~{N}-[(2~{S})-2-methyl-4-oxidanyl-1-oxidanylidene-pent-4-en-2-yl]carbamate, GLYCEROL, ... (4 entities in total)
• Functional Keywords: pbp3, penicillin binding proteins, peptidoglycan production, transpeptidation, hydrolase
• Biological source: Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)
• Total number of polymer chains: 1
• Total formula weight: 56936.88

Authors

Newman, H.,Bellini, D.,Dowson, C.G. (deposition date: 2020-02-27, release date: 2020-06-24, Last modification date: 2024-11-06)

Primary citation

Kidd, S.L.,Fowler, E.,Reinhardt, T.,Compton, T.,Mateu, N.,Newman, H.,Bellini, D.,Talon, R.,McLoughlin, J.,Krojer, T.,Aimon, A.,Bradley, A.,Fairhead, M.,Brear, P.,Diaz-Saez, L.,McAuley, K.,Sore, H.F.,Madin, A.,O'Donovan, D.H.,Huber, K.V.M.,Hyvonen, M.,von Delft, F.,Dowson, C.G.,Spring, D.R.
Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion.
Chem Sci, 11:10792-10801, 2020

PubMed Abstract: Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10-14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.

PubMed: 34094333
DOI: 10.1039/d0sc01232g

Experimental method

X-RAY DIFFRACTION (1.7 Å)