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Computational Biology and Bioinformatics in Anti-SARS-CoV-2 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
It is now recognized that the desired effects of most therapeutics are exerted via modulation of multiple targets and pathways [164–167], whereas severe side effects can sometimes be associated with the excessive selectivity of a drug for a single target [168]. Moreover, it deals with pharmaceutical agents characterized by the promiscuous binding to multiple targets and acting on multiple disease pathways, thereby generating different phenotypic or pharmacological effects [167]. Polypharmacology deals with multi-target binding, drug off targeting, and molecular promiscuity, and thereby opposes the “single drug, single target” approach. Therefore, polypharmacology has emerged as a powerful alternative paradigm for development of versatile therapeutic agents capable of modulating multiple biological targets simultaneously, often displaying higher efficacy, less resistance, and an improved safety profile [169]. It is important to emphasize that, while in the past the identification of multi-targeting agents has largely been fortuitous and serendipitous, recent advances in computational sciences enable rational design of drug polypharmacology (reviewed in [167, 170, 171]). Since a single therapeutic can act on multiple targets and a single target can be affected by multiple therapeutics, one can differentiate ligand-based and target-based polypharmacology, whereas network pharmacology integrates multi-omics technologies and systems biology for drug discovery and development [172].
Dealing with frequent hitters in drug discovery: a multidisciplinary view on the issue of filtering compounds on biological screenings
Published in Expert Opinion on Drug Discovery, 2019
Rafael Ferreira Dantas, Tereza Cristina Santos Evangelista, Bruno Junior Neves, Mario Roberto Senger, Carolina Horta Andrade, Sabrina Baptista Ferreira, Floriano Paes Silva-Junior
In this review we will adopt the expression ‘frequent hitter’ (FH) to denote compounds that are frequently (higher than average) found as hits in screening campaigns. FHs may arise from generalized assay interference (see ‘PAINS’ below) or simply be the consequence of molecular promiscuity in ligand-target interactions. Related to the later, there are other concepts such as ‘privileged scaffolds’ (see below), ‘polypharmacology’ [3] and ‘multi-target’ (a drug design strategy [4]). To avoid confusion, we will present below definitions and, when appropriate, some background information on the key terms relevant for the topic of this review.