Covalent Inhibitors as Potent Drugs in Pharmaceutical Industry

Expert-driven In Silico Drug Discovery Solutions
28 July 2021
Andrew Golub
Group Leader, Molecular Design

It has long been recognized that covalent modifiers are crucial to the development of new drugs. For the last two centuries, the field of study covering covalent inhibitors has undergone a great change. Today, approximately 30% of all marketed drugs act as covalent inhibitors. Despite the initial concerns about potential off-target toxicity, covalent inhibitors offer numerous advantages. This is supported by continuous research, especially on cancer targets.

The general concept of covalent inhibitors refers to compounds designed to form a covalent bond with a specific protein target. Depending on the chosen warhead, the covalent bonds can be reversible or irreversible. There have been different warheads that target different amino acid residues, including cysteine, serine, threonine, tyrosine, and lysine among others.

Although the pharmaceutical industry was initially skeptical about covalent inhibitor applications, over the last fifty years, covalent inhibitor development has increased significantly (Fig. 1) [1,2] Numerous drug candidates are proceeding through clinical trials or have been approved by the FDA. Currently, there are about 50 FDA-approved drugs that work as covalent inhibitors.

Number of publications per decade obtained from a search of the term “covalent drug” in SciFinder

Fig. 1 Number of publications per decade obtained from a search of the term “covalent drug” in SciFinder®. Source: RSC Med. Chem., 2020,11, 876-884

The main reasons for the attrition of drug candidates during clinical trials are toxicity and efficacy [3]. Consequently, covalent inhibitors offer several benefits:

  1. increasing efficacy
  2. lowering the dosage
  3. increasing compliance through less frequent administration
  4. minimizing drug resistance
  5. targeting shallow binding sites

It should be noted that there is a connection between each of them. They have high potency, low IC50 values, and long binding duration, which means less frequent and smaller doses are needed in comparison to normal drugs. As a matter of fact, lower dosing frequencies, especially once-daily dosing [4], are associated with improved patient compliance, which can be achieved with covalent inhibitors. Additionally, the use of covalent binders against resistance-prone targets has been shown to have potential advantages.

A brief timeline of covalent drug discovery. Structures of covalent inhibitors are provided along with the enzymes/proteins they inhibit

Fig. 2. A brief timeline of covalent drug discovery. Structures of covalent inhibitors are provided along with the enzymes/proteins they inhibit. Source: ChemMedChem., 2019, 14(9): 889–906.

Covalent inhibitors, however, are considered to have low selectivity because they are highly reactive. On the other hand, some studies have demonstrated their remarkable selectivity. In a study on quinazoline inhibitors [5], it has been found that a targeted small covalent inhibitor suppresses KRAS G12C, and the selectivity was higher than that of allosteric compounds. Similarly, a study [6] on Janus kinases (JAKs) showed high selectivity against JAK3 due to the addition of a covalent warhead in the compound.

However, the disadvantages of covalent inhibitors are also considerable. In particular, they may not be suitable for targets that are rapidly turned over by enzymes or degraded, they may cause drug-induced and/or unexpected toxicity or hypersensitivity, and, finally, covalent inhibitors may lead to difficulties with an appropriate warhead choice.

As our knowledge about the mechanism of action and the reactivity of several types of warheads increases, we may be better prepared to design covalent inhibitors and to help tune their properties so that their disadvantages are minimized.

Approximately 28% of covalent inhibitors on the market are used in oncology-related targets, 23% for CNS disorders and cardiovascular diseases, 21% for infections (mostly β-lactam antibiotics), and 11% for gastrointestinal diseases (Fig. 3).

Approved covalent drugs by therapeutic indication

Fig. 3 Approved covalent drugs by therapeutic indication. Source: RSC Med. Chem., 2020,11, 876-884

There have been 14 new covalent drugs approved in the last 10 years. Nonetheless, two of them, telaprevir and boceprevir, were discontinued in 2014 and 2015 due to their low demand compared to newer generation anti-HCV agents. Nine of these newly approved covalent drugs have an α,β-unsaturated carbonyl as their warhead.

As it can be seen, in the past decade, the rational development of covalent inhibitors has steadily increased. The covalent warhead toolbox has been expanded with numerous representatives that can selectively target specific amino acid residues. A total of 50 covalent compounds are on the market or undergoing advanced clinical trials. Providing more data are generated regarding covalent drugs' safety and efficacy, the future optimization and rational development of these products will be made possible. Therefore, covalent inhibitors remain a popular choice for difficult targets, including protein-protein interactions, where non-covalent inhibitors may not provide sufficient selectivity. Furthermore, the recent examples of PROTACs with covalent warheads illustrate their capability in new areas of application.

At Life Chemicals, we have designed a number of screening compound libraries to offer for your research needs in covalent inhibitor discovery (please see the list below). Our medicinal and computational chemistry experts have selected only those compounds for each library that contain at least one covalent warhead and preserve their drug-like properties. The targeted amino acid residues are indicated for each compound.

Covalent Inhibitor Libraries

Please, contact us at orders@lifechemicals.comfor any details and quotations.

Please, visit our Website for more information and download SD files with compound structures in the Downloads section. Custom compound selection based on specific parameters can be performed on request, with competitive pricing and the most convenient terms provided.


  1. J. Singh, R. C. Petter, T. A. Baillie, and A. Whitty, Nat. Rev. Drug Discovery, 2011, 10, 307 —317.
  2. R. A. Bauer Drug Discovery Today, 2015, 20, 1061 —1073
  3. I. Kola and J. Landis, Nat. Rev. Drug Discovery, 2004, 3, 711 —716
  4. C. I. Coleman , B. Limone , D. M. Sobieraj , S. Lee , M. S. Roberts , R. Kaur and T. Alam , J. Manage. Care Pharm., 2012, 18 , 527 —539
  5. M. Zeng , J. Lu , L. Li , F. Feru , C. Quan , T. W. Gero , S. B. Ficarro , Y. Xiong , C. Ambrogio and R. M. Paranal , Cell Chem. Biol., 2017, 24 , 1005 —1016. e1003
  6. J. Kempson, D. Ovalle, J. Guo, S. T. Wrobleski, S. Lin, S. H. Spergel, J. J.-W. Duan , B. Jiang , Z. Lu and J. Das , Bioorg. Med. Chem. Lett., 2017, 27, 4622 —4625
28 July 2021, 13:21 Andrew Golub Computational Chemistry

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