AUTHOR=Bian Yuemin , Kwon Jason J. , Liu Cong , Margiotta Enrico , Shekhar Mrinal , Gould Alexandra E. 

TITLE=Target-driven machine learning-enabled virtual screening (TAME-VS) platform for early-stage hit identification

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1163536

DOI=10.3389/fmolb.2023.1163536

ISSN=2296-889X

ABSTRACT=High-throughput screening (HTS) methods enable the empirical evaluation of a large scale of compounds and can be augmented by virtual screening (VS) techniques to save time and costs by nominating potential active compounds for experimental testing. Structure-based and ligand-based VS approaches have been extensively studied and applied in drug discovery practice with proven outcomes in advancing candidate molecules. However, the experimental data required for VS is costly, and hit identification in an effective and efficient manner is particularly challenging during early-stage drug discovery for novel protein targets. Herein, we present our TArget-driven Machine learning-Enabled VS (TAME-VS) platform, that leverages existing chemical databases of bioactive molecules to modularly facilitate hit finding. Our methodology enables bespoke hit identification campaigns through a user-defined protein target. The input target ID is utilized to perform a homology-based target expansion, followed by compound retrieval from a large compilation of molecules with experimentally validated activity. Compounds are subsequently vectorized and adopted for machine learning (ML) model training. These ML models are deployed to perform model inferential virtual screening, and compounds are nominated based on predicted activity. Our platform was retrospectively validated across ten diverse protein targets and demonstrated clear predictive power. The implemented methodology provides a flexible and efficient approach that is accessible by a wide range of users. The TAME-VS platform is publicly available at https://github.com/bymgood/Target-driven-ML-enabled-VS to facilitate early-stage hit identification.