Decomposing compounds enables reconstruction of interaction fingerprints for structure-based drug screening

Research output: Contribution to journalResearch articleContributedpeer-review


BACKGROUND: Structure-based drug repositioning has emerged as a promising alternative to conventional drug development. Regardless of the many success stories reported over the past years and the novel breakthroughs on the AI-based system AlphaFold for structure prediction, the availability of structural data for protein-drug complexes remains very limited. Whereas the chemical libraries contain millions of drug compounds, the vast majority of them do not have structures to crystallized targets,and it is, therefore, impossible to characterize their binding to targets from a structural view. However, the concept of building blocks offers a novel perspective on the structural problem. A drug compound is considered a complex of small chemical blocks or fragments, which confer the relevant properties to the drug and have a high proportion of functional groups involved in protein binding. Based on this, we propose a novel approach to expand the scope of structure-based repositioning approaches by transferring the structural knowledge from a fragment to a compound level.

RESULTS: We fragmented over 100,000 compounds in the Protein Data Bank (PDB) and characterized the structural binding mode of 153,000 fragments to their crystallized targets. Using the fragment's data, we were able to artificially reconstruct the binding mode of over 7,800 complexes between ChEMBL compounds and their known targets, for which no structural data is available. We proved that the conserved binding tendency of fragments, when binding to the same targets, highly influences the drug's binding specificity and carries the key information to reconstruct full drugs binding mode. Furthermore, our approach was able to reconstruct multiple compound-target pairs at optimal thresholds and high similarity to the actual binding mode.

CONCLUSIONS: Such reconstructions are of great value and benefit structure-based drug repositioning since they automatically enlarge the technique's scope and allow exploring the so far 'unexplored compounds' from a structural perspective. In general, the transfer of structural information is a promising technique that could be applied to any chemical library, to any compound that has no crystal structure available in PDB, and even to transfer any other feature that may be relevant for the drug discovery process and that due to data limitations is not yet fully available. In that sense, the results of this work document the full potential of structure-based screening even beyond PDB.


Original languageEnglish
Article number17
Pages (from-to)17
JournalJournal of cheminformatics
Issue number1
Publication statusPublished - Dec 2022

External IDs

Scopus 85126544446
PubMed 35292113
dblp journals/jcheminf/AdasmeBAS22
Mendeley be02fb32-49b1-338e-91f8-e9e40dbd2b6a
WOS 000769469000001
ORCID /0000-0003-2848-6949/work/141543346



  • Binding mode, Fragments, Interactions fingerprint, Non-covalent interactions, Structural data

Library keywords