New techniques and strategies in drug discovery (2020–2024 update)

Abstract

In the realm of drug discovery, recent advancements have paved the way for innovative approaches and methodologies. This comprehensive review encapsulates six distinct yet interrelated mini-reviews, each shedding light on novel strategies in drug development. (a) The resurgence of covalent drugs is highlighted, focusing on the targeted covalent inhibitors (TCIs) and their role in enhancing selectivity and affinity. (b) The potential of the quantum mechanics-based computational aid drug design (CADD) tool, Cov_DOX, is introduced for predicting protein-covalent ligand binding structures and affinities. (c) The scaffolding function of proteins is proposed as a new avenue for drug design, with a focus on modulating protein-protein interactions through small molecules and proteolysis targeting chimeras (PROTACs). (d) The concept of pro-PROTACs is explored as a promising strategy for cancer therapy, combining the principles of prodrugs and PROTACs to enhance specificity and reduce toxicity. (e) The design of prodrugs through carbon-carbon bond cleavage is discussed, offering a new perspective for the activation of drugs with limited modifiable functional groups. (f) The targeting of programmed cell death pathways in cancer therapies with small molecules is reviewed, emphasizing the induction of autophagy-dependent cell death, ferroptosis, and cuproptosis. These insights collectively contribute to a deeper understanding of the dynamic landscape of drug discovery.