Computer aided drug design in the development of proteolysis targeting chimeras

Proteolysis targeting chimeras represent a class of drug molecules with a number of attractive properties, most notably a potential to work for targets that, so far, have been in-accessible for conventional small molecule inhibitors. Due to their different mechanism of action, and physico-chemical properties, many of the methods that have been designed and applied for computer aided design of traditional small molecule drugs are not applicable for proteolysis targeting chimeras. Here we review recent developments in this field focusing on three aspects: de-novo linker-design, estimation of absorption for beyond-rule-of-5 compounds, and the generation and ranking of ternary complex structures. In spite of this field still being young, we find that a good number of models and algorithms are available, with the potential to assist the design of such compounds in-silico, and accelerate applied pharmaceutical research.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Proteolysis targeting chimeras (PROTACs) are a promising class of drug molecules that have the potential to target previously inaccessible proteins. In this review, we discuss recent advancements in PROTAC design, including linker design, absorption estimation for compounds that violate the rule-of-5, and the generation and ranking of ternary complex structures. Despite being a relatively new field, there are already several models and algorithms available to aid in silico design and accelerate pharmaceutical research.