Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors

Jílková, Adéla; Rubešová, Petra; Fanfrlík, Jindřich; Fajtová, Pavla; Řezáčová, P.; Brynda, J.; Lepšı́k, Martin; Mertlíková‐Kaiserová, Helena; Emal, Cory D.; Renslo, Adam R.; Roush, William; Horn, Martin; Caffrey, Conor R.

doi:10.1021/acsinfecdis.0c00501

Cited by 18 publications

(34 citation statements)

References 70 publications

(146 reference statements)

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“…Females secreted several cathepsins more abundantly than males, including SmCB1 (Q8MNY2_SCHMA), which is known to be secreted from the gut of schistosomes and to contribute to Th2 polarization responses (de Oliveira Fraga et al, 2010). This enzyme has been validated as a potent anti-schistosome chemotherapeutic target (Abdulla et al, 2007;Jilkova et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke,Schistosoma mansoni

Kenney

Mann

Tanno

et al. 2022

Preprint

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Intricate molecular communication between the schistosome (flatworms) and its mammalian host, as well as between paired male and female schistosomes has shaped the secreted proteome of these flatworms. Whereas the schistosome egg is responsible for the disease manifestations of chronic schistosomiasis, the long lived, adult female and male stages also release mediators that facilitate their long-lived intra-vascular existence in a hostile niche where they are bathed in immune cells and effector molecules. However, despite their importance, no studies have focused on analysing the excretory/secretory products (ESPs) from adult schistosomes. Herein, ESPs from cultured Schistosoma mansoni male or female adult worms were identified, quantified, compared and contrasted using a label-free proteomic approach. Approximately 1,000 proteins were identified, from which almost 800 could be finally quantified. Considering the proteins uniquely identified and proteins with a significantly regulated expression pattern in male or female flukes, a total of 370 and 140 proteins were more abundantly secreted by males and females, respectively. Using functional analysis networks showing the gene ontology terms and KEGG pathways with the highest significance, we observed that male schistosomes secrete proteins related to carbohydrate metabolism, cytoskeletal organisation more abundantly than females, while female worms secreted more hydrolases and proteins involved in cellular homeostasis than males. This analysis doubles the number of previously reported ESPs from S. mansoni, contributing to a better understanding of the host-parasite dynamic interactions. Furthermore, these findings expand potential vaccine and diagnostic candidates for this neglected tropical disease pathogen, which will enable deeper understanding of the molecular communication critical to parasitism.

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Section: Discussionmentioning

confidence: 99%

Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke,Schistosoma mansoni

Kenney

Mann

Tanno

et al. 2022

Preprint

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“…60 It was resolved at 1.91 Å and complexed with the ligand WRR391. 55,61 The protein crystal structure was prepared using the Protein Preparation wizard tool of Schrodinger before docking to solve many issues related to protein. 62 This procedure results in reassignment bond orders, the addition of hydrogens, recognition of disulfide bonds, filling of missing loops and side chains, and correction of any misidentified components.…”

Section: Preparation Of the Proteinmentioning

confidence: 99%

“…54 The X-ray structure of SmCB1 in combination with WRR-391 was recently determined by Jlkova group. 55 Structure-based drug discovery is among the most popular and commonly utilized methods in the drug discovery process. 56 As an outcome, the length and expense of medication research and development can be reduced.…”

Section: Introductionmentioning

confidence: 99%

De Novo Design of Cathepsin B1 Inhibitors as Potential Anti-Schistosomal Agents Using Computational Studies

Alzain¹,

Elbadwi²

2022

AABC

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Background: Schistosomiasis is the world's second most devastating disease after malaria and the leading cause of disease and mortality for more than 200 million people in developing countries. Cysteine proteases, in particular SmCB1, are the most well-researched biological targets for this disorder. Objective: To apply computational techniques to design new antischistosomal agents against SmCB1 protein with favorable pharmacokinetic properties. Methods: The smCB1 receptor-based pharmacophore model was created and used to screen 567,000 fragments from the Enamine library. The best scoring fragments have been linked to build novel compounds that were subjected to molecular docking, MM-GBSA free energy estimation, ADME prediction, and molecular dynamics. Results: A seven-point pharmacophore hypothesis ADDDRRR was created. The developed hypothesis was used to screen 1.3 M fragment conformations. Among them, 23,732 fragments matched the hypothesis and screened against the protein. The top 50 fragments were used to design new 7745 compounds using the Breed ligand panel which were subjected to docking and MMGBSA binding energy. This led to the identification of 10 compounds with better docking scores (−8.033-−7.483 kcal/mol) and lower-bound free energies (−58.49 -−40.02 kcal/mol) compared to the reference bound ligand. Most of the designed compounds demonstrated good drug-like properties. Concerning Molecular dynamics (MD) simulation results, a low root mean square deviation (RMSD) range (0.25-1.2 Å) was found for the top 3 complexes which indicated their stability. Conclusion:We identified compounds that could be potential candidates in the search for novel Schistosoma mansoni inhibitors by targeting SmCB1 utilizing various computational tools. Three newly designed compounds namely breed 1, 2, and 3 showed promising affinity to the target as well as favorable drug-like properties which might be considered potential anti-schistosomal agents.

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“…Some of these applied scoring methods based on quantum mechanics (QM) to describe important interactions between vinyl sulfone chemotype inhibitors and SmCB1 (163). Furthermore, these inhibitors were important to map druggable hot spots in SmCB1 (150). The vinyl sulfones inhibitors also showed desirable properties such as activity in phenotypic assays, selectivity for SmCB1 over human cathepsin B and metabolic stability.…”

Section: Target-based Screeningmentioning

confidence: 99%

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

et al. 2021

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Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and affects over 200 million people worldwide. The control and treatment of this neglected tropical disease is based on a single drug, praziquantel, which raises concerns about the development of drug resistance. This, and the lack of efficacy of praziquantel against juvenile worms, highlights the urgency for new antischistosomal therapies. In this review we focus on innovative approaches to the identification of antischistosomal drug candidates, including the use of automated assays, fragment-based screening, computer-aided and artificial intelligence-based computational methods. We highlight the current developments that may contribute to optimizing research outputs and lead to more effective drugs for this highly prevalent disease, in a more cost-effective drug discovery endeavor.

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Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors

Cited by 18 publications

References 70 publications

Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke,Schistosoma mansoni

Differential excretory/secretory proteome of the adult female and male stages of the human blood fluke,Schistosoma mansoni

De Novo Design of Cathepsin B1 Inhibitors as Potential Anti-Schistosomal Agents Using Computational Studies

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

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