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

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

  • J Cheminform. 2021 Nov 23;13(1):90. doi: 10.1186/s13321-021-00567-3.
Merveille Eguida 1 Didier Rognan 2
Affiliations

Affiliations

  • 1 Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, 67400, Illkirch, France.
  • 2 Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, 67400, Illkirch, France. rognan@unistra.fr.
Abstract

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.

Keywords

Binding sites; Point cloud registration; Similarity.

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