5OGR

Structure of cathepsin B1 from Schistosoma mansoni in complex with WRR286 inhibitor

Summary for 5OGR

• Entry DOI: 10.2210/pdb5ogr/pdb
• Related: 3QSD 3S3Q 3S3R 4I04 4I05 4I07
• Descriptor: Cathepsin B-like peptidase (C01 family), 3-[[N-[4-METHYL-PIPERAZINYL]CARBONYL]-PHENYLALANINYL-AMINO]-5-PHENYL-PENTANE-1-SULFONIC ACID BENZYLOXY-AMIDE, ACETATE ION, ... (4 entities in total)
• Functional Keywords: protease, parasite, inhibitor, vinyl sulfone, hydrolase
• Biological source: Schistosoma mansoni (Blood fluke)
• Total number of polymer chains: 3
• Total formula weight: 87564.27

Authors

Jilkova, A.,Rezacova, P.,Brynda, J.,Mares, M. (deposition date: 2017-07-13, release date: 2018-11-21, Last modification date: 2024-11-06)

Primary citation

Jilkova, A.,Rubesova, P.,Fanfrlik, J.,Fajtova, P.,Rezacova, P.,Brynda, J.,Lepsik, M.,Mertlikova-Kaiserova, H.,Emal, C.D.,Renslo, A.R.,Roush, W.R.,Horn, M.,Caffrey, C.R.,Mares, M.
Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors.
Acs Infect Dis., 2020

PubMed Abstract: Schistosomiasis, a parasitic disease caused by blood flukes of the genus , is a global health problem with over 200 million people infected. Treatment relies on just one drug, and new chemotherapies are needed. cathepsin B1 (SmCB1) is a critical peptidase for the digestion of host blood proteins and a validated drug target. We screened a library of peptidomimetic vinyl sulfones against SmCB1 and identified the most potent SmCB1 inhibitors reported to date that are active in the subnanomolar range with second order rate constants () of ∼2 × 10 M s. High resolution crystal structures of the two best inhibitors in complex with SmCB1 were determined. Quantum chemical calculations of their respective binding modes identified critical hot spot interactions in the S1' and S2 subsites. The most potent inhibitor targets the S1' subsite with an -hydroxysulfonic amide moiety and displays favorable functional properties, including bioactivity against the pathogen, selectivity for SmCB1 over human cathepsin B, and reasonable metabolic stability. Our results provide structural insights for the rational design of next-generation SmCB1 inhibitors as potential drugs to treat schistosomiasis.

PubMed: 33175511
DOI: 10.1021/acsinfecdis.0c00501

Experimental method

X-RAY DIFFRACTION (1.55 Å)