Unexpected similarity between HIV-1 reverse transcriptase and tumor necrosis factor binding sites revealed by computer vision.
Merveille EguidaDidier RognanPublished in: Journal of cheminformatics (2021)
Rationalizing the identification of hidden similarities across the repertoire of druggable protein cavities remains a major hurdle to a true proteome-wide structure-based discovery of novel drug candidates. We recently described a new computational approach (ProCare), inspired by numerical image processing, to identify local similarities in fragment-based subpockets. During the validation of the method, we unexpectedly identified a possible similarity in the binding pockets of two unrelated targets, human tumor necrosis factor alpha (TNF-α) and HIV-1 reverse transcriptase (HIV-1 RT). Microscale thermophoresis experiments confirmed the ProCare prediction as two of the three tested and FDA-approved HIV-1 RT inhibitors indeed bind to soluble human TNF-α trimer. Interestingly, the herein disclosed similarity could be revealed neither by state-of-the-art binding sites comparison methods nor by ligand-based pairwise similarity searches, suggesting that the point cloud registration approach implemented in ProCare, is uniquely suited to identify local and unobvious similarities among totally unrelated targets.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- rheumatoid arthritis
- hepatitis c virus
- hiv aids
- men who have sex with men
- endothelial cells
- deep learning
- small molecule
- induced pluripotent stem cells
- high throughput
- pluripotent stem cells
- cord blood
- single cell
- transcription factor
- machine learning