TY - JOUR
T1 - Predicting the Likelihood of Molecules to Act as Modulators of Protein-Protein Interactions
AU - Wolk, Omri
AU - Goldblum, Amiram
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2023/1/9
Y1 - 2023/1/9
N2 - Targeting protein-protein interactions (PPIs) by small molecule modulators (iPPIs) is an attractive strategy for drug therapy, and some iPPIs have already been introduced into the clinic. Blocking PPIs is however considered to be a more difficult task than inhibiting enzymes or antagonizing receptor activity. In this paper, we examine whether it is possible to predict the likelihood of molecules to act as iPPIs. Using our in-house iterative stochastic elimination (ISE) algorithm, we constructed two classification models that successfully distinguish between iPPIs from the iPPI-DB database and decoy molecules from either the Enamine HTS collection (ISE 1) or the ZINC database (ISE 2). External test sets of iPPIs taken from the TIMBAL database and decoys from Enamine HTS or ZINC were screened by the models: the area under the curve for the receiver operating characteristic curve was 0.85-0.89, and the Enrichment Factor increased from an initial 1 to as much as 66 for ISE 1 and 57 for ISE 2. Screening of the Enamine HTS and ZINC data sets through both models results in a library of ∼1.3 million molecules that pass either one of the models. This library is enriched with iPPI candidates that are structurally different from known iPPIs, and thus, it is useful for target-specific screenings and should accelerate the discovery of iPPI drug candidates. The entire library is available in Table S6.
AB - Targeting protein-protein interactions (PPIs) by small molecule modulators (iPPIs) is an attractive strategy for drug therapy, and some iPPIs have already been introduced into the clinic. Blocking PPIs is however considered to be a more difficult task than inhibiting enzymes or antagonizing receptor activity. In this paper, we examine whether it is possible to predict the likelihood of molecules to act as iPPIs. Using our in-house iterative stochastic elimination (ISE) algorithm, we constructed two classification models that successfully distinguish between iPPIs from the iPPI-DB database and decoy molecules from either the Enamine HTS collection (ISE 1) or the ZINC database (ISE 2). External test sets of iPPIs taken from the TIMBAL database and decoys from Enamine HTS or ZINC were screened by the models: the area under the curve for the receiver operating characteristic curve was 0.85-0.89, and the Enrichment Factor increased from an initial 1 to as much as 66 for ISE 1 and 57 for ISE 2. Screening of the Enamine HTS and ZINC data sets through both models results in a library of ∼1.3 million molecules that pass either one of the models. This library is enriched with iPPI candidates that are structurally different from known iPPIs, and thus, it is useful for target-specific screenings and should accelerate the discovery of iPPI drug candidates. The entire library is available in Table S6.
UR - http://www.scopus.com/inward/record.url?scp=85144154471&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.2c00920
DO - 10.1021/acs.jcim.2c00920
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C2 - 36512704
AN - SCOPUS:85144154471
SN - 1549-9596
VL - 63
SP - 126
EP - 137
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 1
ER -