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Review
. 2020 Jul 2;11(8):876-884.
doi: 10.1039/d0md00154f. eCollection 2020 Aug 1.

Covalent inhibitors: a rational approach to drug discovery

Fandi Sutanto  1 , Markella Konstantinidou  1 , Alexander Dömling  1
Affiliations
Review

Covalent inhibitors: a rational approach to drug discovery

Fandi Sutanto et al. RSC Med Chem. .

Abstract

Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent inhibitors in the late 18th century, the field has advanced significantly and currently about 30% of the marketed drugs are covalent inhibitors. The numerous advantages of covalent inhibitors are counteracting the initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. The aim of this review is to provide a short historic overview and focus on recently developed covalent inhibitors (2011-2019), including structural aspects and examples on challenging targets.

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Figures

Fig. 1
Fig. 1. General mechanism of covalent interaction between a small molecule and its target.
Fig. 2
Fig. 2. Number of publications per decade obtained from a search of the term “covalent drug” in SciFinder®.
Fig. 3
Fig. 3. A historic overview of covalent inhibitors and their approval dates. The warheads are highlighted in red.
Fig. 4
Fig. 4. Approved covalent drugs by therapeutic indication.
Fig. 5
Fig. 5. Abiraterone complex with human cytochrome P450 CYP17A1 (PDB ID 3RUK). Abiraterone is shown as cyan sticks and HEM-600 is shown as yellow sticks.
Fig. 6
Fig. 6. Chemical structures of covalent inhibitors and their crystal structures with the NS3/4A protease complex (a) telaprevir binding to Ser-1139 (PDB ID 3SV6), (b) narlaprevir (PDB ID ; 3LON), and (c) boceprevir (PDB ID ; 3LOX) binding to Ser-139. Inhibitors are shown as cyan sticks and Ser-1139, Ser-139 are shown as yellow sticks.
Fig. 7
Fig. 7. Chemical structures and binding modes with the target protein: (a) dimethyl fumarate binding to Cys-599 (PDB ID 5O1S), (b) EGFR kinase inhibitor dacomitinib, binding Cys-797 (PDB ID ; 4I24), (c) ibrutinib (PDB ID ; 5P9J), and (d) zanubrutinib (PDB ID ; 6J6M) binding to Cys-481 of BTK. Inhibitors are shown as cyan sticks and Cys-599, Cys-797, Cys-481 are shown as yellow sticks.
Fig. 8
Fig. 8. Chemical structures and binding modes with the target protein: (a) AMG510 (PDB ID 6OIM) and (b) MRTX-849 (PDB ID ; 6UT0) binding to Cys-12 of KRAS (G12C). Inhibitors are shown as cyan sticks and Cys-12 is shown as yellow sticks, (c) structure of CRBN–KRASG12C lead PROTAC described by Gray et al.
Fig. 9
Fig. 9. Structure of ibrutinib analogue 1, PLS-123, and PLS-123 analogue 2.
Fig. 10
Fig. 10. Structure of PROTAC a targeting BTK.
None
Fandi Sutanto
None
Markella Konstantinidou
None
Alexander Dömling
See this image and copyright information in PMC

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