Novel starting points for fragment-based drug design against mycobacterial thioredoxin reductase identified using crystallographic fragment screening.
Friederike Theresa FüsserJan WollenhauptManfred S WeissDaniel KümmelOliver KochPublished in: Acta crystallographica. Section D, Structural biology (2023)
The increasing number of people dying from tuberculosis and the existence of extensively drug-resistant strains has led to an urgent need for new antituberculotic drugs with alternative modes of action. As part of the thioredoxin system, thioredoxin reductase (TrxR) is essential for the survival of Mycobacterium tuberculosis (Mtb) and shows substantial differences from human TrxR, making it a promising and most likely selective target. As a model organism for Mtb, crystals of Mycobacterium smegmatis TrxR that diffracted to high resolution were used in crystallographic fragment screening to discover binding fragments and new binding sites. The application of the 96 structurally diverse fragments from the F2X-Entry Screen revealed 56 new starting points for fragment-based drug design of new TrxR inhibitors. Over 200 crystal structures were analyzed using FragMAXapp, which includes processing and refinement by largely automated software pipelines and hit identification via the multi-data-set analysis approach PanDDA. The fragments are bound to 11 binding sites, of which four are positioned at binding pockets or important interaction sites and therefore show high potential for possible inhibition of TrxR.
Keyphrases
- mycobacterium tuberculosis
- drug resistant
- multidrug resistant
- pulmonary tuberculosis
- high resolution
- acinetobacter baumannii
- high throughput
- endothelial cells
- palliative care
- escherichia coli
- machine learning
- emergency department
- drug induced
- deep learning
- electronic health record
- adverse drug
- dna binding
- risk assessment
- transcription factor
- pseudomonas aeruginosa
- room temperature
- human health
- cystic fibrosis
- human immunodeficiency virus
- high speed