Drug Discovery Paradigms: Phenotypic-Based Drug Discovery

Abstract

A drug discovery and development project typically starts with the identifcation of novel active scaffolds, i.e., core chemical structures with a desired biological effect. Beyond serendipitous discoveries and fndings based on ethnopharmacology/traditional medicine, drug discovery in the modern age has been guided by two fundamental screening philosophies (implementedwhether through in silico, in vitro or less often, in vivo approximations).Occasionally, novel chemotypes can be designed de novo by searching for complementary features to a binding site in a predefned drug target. Historically, systematic screening for new active compounds comprised henotypic screening assays (e.g., against a collection of microorganisms, animal models of disease, or cellular models). Later, the interest of the pharmaceutical companies experienced a substantial shift toward target-focused approximations in which exquisitely selective compounds were sought, usually through high-throughput screening. There, the test compounds were typically confronted with some biological entity, usually a protein, to identify those which could modulate such biomolecule. Nevertheless, as target-focused approximation failed to deliver the expectations, especially when pursuing therapies for complex disorders, renewed interest in phenotypic screening was observed in the pharmaceutical community, supported by a network pharmacology paradigm, high-content screening, small animal models, and organoidsand other advanced cell culture platforms.Phenotypic screening is advantageous in several respects. Remarkably, it can detect drugs with novel, unsuspected modes of action and/or complex pharmacology (e.g., multi-target drugs), and it can also provide hits with an adequate balance of an array of pharmaceutically relevant features, including effcacy, safety, and bioavailability, which in turn could lead to better translatability.