Crystal structure of O-Acetylserine sulfhydralase (OASS) isoform 3 from Entamoeba histolytica: Pharmacophore-based virtual screening and validation of novel inhibitors
| Autor: | Ramachandran Vijayan, Khushboo Kumari, Priya Tomar, Sudhaker Dharavath, Samudrala Gourinath |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Gene isoform
Models Molecular Drug Evaluation Preclinical Crystallography X-Ray 01 natural sciences 03 medical and health sciences Entamoeba histolytica chemistry.chemical_compound Structure-Activity Relationship parasitic diseases Drug Discovery Enzyme Inhibitors 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Virtual screening Cysteine Synthase biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry General Medicine biology.organism_classification 0104 chemical sciences Isoenzymes Enzyme chemistry Biochemistry Docking (molecular) Pharmacophore O-Acetylserine Drug Screening Assays Antitumor Cysteine |
| Zdroj: | European journal of medicinal chemistry. 192 |
| ISSN: | 1768-3254 |
| Popis: | The l -cysteine is crucial for growth, survival, defense against oxidative stress, and pathogenesis of Entamoeba histolytica. The de novo biosynthesis of l -cysteine in E. histolytica, has a two-step pathway, where O-acetylserine sulfhydrylase (OASS) catalyses the last step by converting OAS to l -cysteine. This pathway is absent in humans and hence represents a promising target for novel therapeutics. E. histolytica expresses three isoforms of OASS and knockdown studies showed the importance of these enzymes for the survival of the pathogen. Here, we report the crystal structure of OASS isoform 3 from E. histolytica to 1.54 A resolution. The active site geometries and kinetics of EhOASS3 and EhOASS1 structures were found to be very similar. Small-molecule libraries were screened against EhOASS3 and compounds were shortlisted based on the docking scores. F3226-1387 showed best inhibition with IC50 of 38 μM against EhOASS3 and was able to inhibit the growth of the organism to 72%. |
| Databáze: | OpenAIRE |
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