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Identification of inhibitors of the Schistosoma mansoni VKR2 kinase domain

DOI: 10.1021/acsmedchemlett.2c00248 DOI Help

Authors: Indran Mathavan (Imperial College London; Research Complex at Harwell) , Lawrence J. Liu (University of California San Diego) , Sean W. Robinson (Kinetic Discovery Ltd) , Nelly El-Sakkary (University of California San Diego) , Adam Jo J. Elatico (University of the Philippines Diliman) , Darwin Gomez (University of the Philippines Diliman) , Ricky Nellas (University of the Philippines Diliman) , Raymond J. Owens (The Rosalind Franklin Institute; The Wellcome Centre for Human Genetics, University of Oxford) , William Zuercher (UNC Eshelman School of Pharmacy) , Iva Navratilova (Kinetic Discovery Ltd) , Conor R. Caffrey (University of California San Diego) , Konstantinos Beis (Imperial College London; Research Complex at Harwell)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 77

State: Published (Approved)
Published: October 2022
Diamond Proposal Number(s): 12579

Open Access Open Access

Abstract: Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.

Journal Keywords: kinase domain; drug discovery; inhibitor; Schistosoma; schistosomiasis; crystal structure; docking; inhibition of autophosphorylation

Diamond Keywords: Schistosomiasis

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 07/10/2022 08:16


Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)