Accelerating drug discovery and repurposing by combining transcriptional signature connectivity with docking.

We present an in silico approach for drug discovery, dubbed connectivity enhanced structure activity relationship (ceSAR). Building on the landmark LINCS library of transcriptional signatures of drug-like molecules and gene knockdowns, ceSAR combines cheminformatic techniques with signature concordance analysis to connect small molecules and their targets and further assess their biophysical compatibility using molecular docking. Candidate compounds are first ranked in a target structure-independent manner, using chemical similarity to LINCS analogs that exhibit transcriptomic concordance with a target gene knockdown. Top candidates are subsequently rescored using docking simulations and machine learning-based consensus of the two approaches. Using extensive benchmarking, we show that ceSAR greatly reduces false-positive rates, while cutting run times by multiple orders of magnitude and further democratizing drug discovery pipelines. We further demonstrate the utility of ceSAR by identifying and experimentally validating inhibitors of BCL2A1, an important antiapoptotic target in melanoma and preterm birth-associated inflammation.

Connecting omics signatures and revealing biological mechanisms with iLINCS.

There are only a few platforms that integrate multiple omics data types, bioinformatics tools, and interfaces for integrative analyses and visualization that do not require programming skills. Here we present iLINCS ( http://ilincs.org ), an integrative web-based platform for analysis of omics data and signatures of cellular perturbations. The platform facilitates mining and re-analysis of the large collection of omics datasets (>34,000), pre-computed signatures (>200,000), and their connections, as well as the analysis of user-submitted omics signatures of diseases and cellular perturbations. iLINCS analysis workflows integrate vast omics data resources and a range of analytics and interactive visualization tools into a comprehensive platform for analysis of omics signatures. iLINCS user-friendly interfaces enable execution of sophisticated analyses of omics signatures, mechanism of action analysis, and signature-driven drug repositioning. We illustrate the utility of iLINCS with three use cases involving analysis of cancer proteogenomic signatures, COVID 19 transcriptomic signatures and mTOR signaling.