Advances in -omics and data mining technologies have enabled the creation of more high-throughput, high-dimensional biological profiles, or in short biosignatures. These biosignatures can be, for instance, experimental high-content-imaging biosignatures, transcriptomics biosignatures, assay endpoint biosignatures, and virtual-assay-endpoint biosignatures, with using one or multiple biosignatures per compound. Biosignatures aim at enriching traditional drug design approaches, as they contain additional information about biological-systems and phenotypic-response relationships. This innovative paradigm is called Biosignature-Based Drug Design (BBDD). We will show that Ligand-Based Drug Design (LBDD) and Structure-Based Drug Design (SBDD) can greatly benefit when complemented by BBDD. We will highlight the medicinal chemistry applications of BBDD, which can be used to design biosignature diverse libraries, biosignature hit enrichment strategies, and biosignature mode of action enrichments or deletions for hit-to-lead and lead-optimization programs. We will also highlight that toxicities can be considered as additional phenotypes and their rationalization is accessible by the same BBDD paradigm.<br/>Biosignatures capture disease or toxic states, or are induced by compounds or gene perturbations. Thus, biosignatures serve as a universal language between multiple design rationales and enable leveraging across drug design projects due to their multivariate nature. The sentences that are formed with such a language depend on the expert using it, as well as the words available per biosignature. For example -- in contrast to LBDD and SBDD -- BBDD uses particular biosignatures to capture compounds that are inversely correlated to a disease-state. These inversely correlated compounds appear to revert the disease phenotype, and therefore, are relevant compounds for further medicinal chemistry optimization.

Biosignature-based drug design: A new drug design paradigm

255th National Meeting (2018)

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