Contrastive learning in protein language space predicts interactions between drugs and protein targets.
Proc Natl Acad Sci U S A
; 120(24): e2220778120, 2023 Jun 13.
Article
in En
| MEDLINE
| ID: mdl-37289807
ABSTRACT
Sequence-based prediction of drug-target interactions has the potential to accelerate drug discovery by complementing experimental screens. Such computational prediction needs to be generalizable and scalable while remaining sensitive to subtle variations in the inputs. However, current computational techniques fail to simultaneously meet these goals, often sacrificing performance of one to achieve the others. We develop a deep learning model, ConPLex, successfully leveraging the advances in pretrained protein language models ("PLex") and employing a protein-anchored contrastive coembedding ("Con") to outperform state-of-the-art approaches. ConPLex achieves high accuracy, broad adaptivity to unseen data, and specificity against decoy compounds. It makes predictions of binding based on the distance between learned representations, enabling predictions at the scale of massive compound libraries and the human proteome. Experimental testing of 19 kinase-drug interaction predictions validated 12 interactions, including four with subnanomolar affinity, plus a strongly binding EPHB1 inhibitor (KD = 1.3 nM). Furthermore, ConPLex embeddings are interpretable, which enables us to visualize the drug-target embedding space and use embeddings to characterize the function of human cell-surface proteins. We anticipate that ConPLex will facilitate efficient drug discovery by making highly sensitive in silico drug screening feasible at the genome scale. ConPLex is available open source at https//ConPLex.csail.mit.edu.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Proteins
/
Drug Discovery
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2023
Document type:
Article
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA