Preprint Review Version 2 Preserved in Portico This version is not peer-reviewed

A Primer on Harnessing Non-enzymatic Posttranslational Modifications for Drug Design

Version 1 : Received: 2 May 2021 / Approved: 5 May 2021 / Online: 5 May 2021 (11:50:39 CEST)
Version 2 : Received: 18 October 2021 / Approved: 19 October 2021 / Online: 19 October 2021 (10:28:15 CEST)

How to cite: Long, M.; Ly, P.; Aye, Y. A Primer on Harnessing Non-enzymatic Posttranslational Modifications for Drug Design. Preprints 2021, 2021050036 (doi: 10.20944/preprints202105.0036.v2). Long, M.; Ly, P.; Aye, Y. A Primer on Harnessing Non-enzymatic Posttranslational Modifications for Drug Design. Preprints 2021, 2021050036 (doi: 10.20944/preprints202105.0036.v2).

Abstract

Of the manifold concepts in drug discovery and design, covalent drugs have re-emerged as one of the most promising over the past 20-or so years. All such drugs harness the ability of a covalent bond to drive an interaction between a target biomolecule, typically a protein, and a small molecule. Formation of a covalent bond necessarily prolongs target engagement, opening avenues to targeting shallower binding sites, protein complexes, and other difficult to drug manifolds, amongst other virtues. This opinion piece discusses frameworks around which to develop covalent drugs. Our argument, based on results from our research program on natural electrophile signaling, is that targeting specific residues innately involved in native signaling programs are ideally poised to be targeted by covalent drugs. We outline ways to identify electrophile-sensing residues, and discuss how studying ramifications of innate signaling by endogenous molecules can provide a means to predict drug mechanism and function and assess on- versus off-target behaviors.

Keywords

Electrophile; Drug Design; Covalent Drug; Chemical Biology

Subject

CHEMISTRY, Analytical Chemistry

Comments (1)

Comment 1
Received: 19 October 2021
Commenter: Phillippe Ly
Commenter's Conflict of Interests: Author
Comment: This includes new two figures to explain T-REX and additional commentary on to further explain the link to biological probes. All new edits are in green text.
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