Unexpected similarity between HIV-1 reverse transcriptase and tumor necrosis factor binding sites revealed by computer vision

• DOI: 10.1186/s13321-021-00567-3
• Publication Date: 2021-11-23T10:03:10Z
• Authors: Merveille Eguida; Didier Rognan
• Keywords: Chemistry; 0303 health sciences; 03 medical and health sciences; Point cloud registration; Binding sites; Information technology; T58.5-58.64; QD1-999; [CHIM.CHEM]Chemical Sciences/Cheminformatics; Similarity; Research Article

AbstractRationalizing 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.