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Structure-Based Design of Targeted Covalent Inhibitors
Structure-Based Design of Targeted Covalent Inhibitors
Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent
inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable
due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent
inhibition shows promise for targets where previous efforts to identify non-covalent small molecule
inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to
increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional
Received 7th February 2018 groups designed to covalently bind to specific sites in a target. In this tutorial review we introduce the
DOI: 10.1039/c7cs00220c broader concept of covalent inhibition, discuss the potential benefits and challenges of such an approach,
and provide an overview of the current status of the field. We also describe some strategies and
rsc.li/chem-soc-rev computational tools to enable successful covalent drug discovery.
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Fig. 1 Aspirin (1) and penicillin G (2), early covalent drugs discovered from
natural products.
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in question is functionally important, and has a slow rate of Covalent compounds tend to undergo extrahepatic clearance
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resynthesis, safety concerns may arise. Hence this is considered more readily than non-covalent compounds, which can result
as both a potential benefit and risk. Likewise, the possibility in lower bioavailability.6 For example, electrophilic covalent
of complete target inactivation can be a potential benefit, but warheads are susceptible to reaction with glutathione, a scavenger
only if that is a desired outcome of the compound profile. for reactive electrophiles that is present in high concentration in
Conversely, if the target protein has a rapid resynthesis rate, cells. Warhead reactivity is therefore an important consideration,
covalent inhibition may result in no significant benefit. representing a balance between maximising target engagement,
One of the major risks associated with covalent inhibitors is whilst minimising extrahepatic clearance.
the possibility of non-specific binding.2 If the covalent warhead
is reactive enough to bind to residues in other proteins,
unpredictable toxicity events can potentially occur. Further- 3. Covalent modification of catalytic
more, covalent warheads are commonly susceptible to meta- residues
bolism, resulting in reactive intermediates that can cause
damage to proteins and DNA. To overcome this challenge, Many disease targets in drug discovery are enzymes. Enzyme
covalent warheads with low intrinsic reactivity are preferred. targets offer the potential for a covalent inhibitor to directly
A further challenge commonly presented by covalent interfere with the reaction mechanism. Covalent inhibitors are
inhibitors is that measuring potency is more complex than often designed to mimic the natural substrate, but have been
for corresponding reversible inhibitors. In the case of reversible modified in such a way that the reaction cannot proceed to
inhibitors, potencies are typically reported in terms of Ki or IC50 completion, and the inhibitor remains covalently bound to the
values. Ki is the inhibitory binding constant and IC50 is enzyme, the latter permanently rendered unable to perform its
the equilibrium concentration of inhibitor at which 50% of the function. A detailed understanding of the enzymatic mechanism
target process has been inhibited. IC50 values for irreversible with the natural substrate is necessary in order to successfully
inhibitors are time-dependent, because no such equilibrium develop such inhibitors. Two example targets that have been
exists; the inhibitor remains in the target binding site until the the subject of covalent inhibition strategies targeting catalytic
protein is degraded, therefore inhibition of the target protein residues are provided here.
will continue to increase until all of the inhibitor is engaged in
binding, or all of the target has been inhibited. Hence, it is 3.1 DPP-IV
challenging to compare the IC50 values of irreversible covalent Proline-specific dipeptidyl aminopeptidase IV (DPP-IV) is a
inhibitors due to the time-dependent nature of the inhibition. serine protease responsible for the degradation of peptide
Therefore it is more useful to consider the potency of covalent hormones, contributing to the regulation of blood glucose
inhibitors in terms of the parameters Ki and kinact (Fig. 6). Here, levels. Inhibition of DPP-IV has been identified as a method
Ki corresponds to the reversible binding of the ligand in the for the treatment of type 2 diabetes.7 The enzyme selectively
binding pocket of the protein and kinact is the kinetic rate cleaves the peptide bond close to the N-terminus where a
constant for the formation of the covalent bond between protein proline (or alanine) is located at the penultimate position, as
and inhibitor. Measuring Ki and kinact is usually more challen- shown in Fig. 7. The binding site of DPP-IV consists of two
ging and labour intensive than measuring IC50 values. pockets (S1 and S2, Fig. 8). The hydrophobic S1 pocket, is highly
The relationship between pharmacokinetics (PK) and specific for proline, and also contains the catalytic triad com-
pharmacodynamics (PD) for irreversible covalent inhibitors prising of Ser630, Asp708 and His740. The S2 pocket can bind
is often more complex to that of reversible inhibitors.5 The any amino acid and contains the Glu205 and Glu206 pair, which
duration of action of a reversible inhibitor will depend on bind to the terminal amino group of the peptide substrate.
how long it remains bound to the target (i.e. residence time) Both covalent and non-covalent inhibitors have been developed
and how quickly it is cleared from the body (i.e. PK). For for DPP-IV. Non-covalent DPP-IV inhibitors, such as sitagliptin (9)
an irreversible inhibitor, the compound will remain bound (Fig. 9), exclusively form non-covalent interactions with the bind-
to the target beyond the point where all of the free drug ing pocket of the enzyme. 9 was the first DPP-IV inhibitor to obtain
has been excreted, and as mentioned above, the PK/PD rela- FDA approval in 2006. Saxagliptin (10) (Fig. 9), is a covalent DPP-IV
tionship is also therefore dependent on the rate of target inhibitor and contains a core resembling proline, but in addition
regeneration. forms a reversible covalent interaction with the enzyme.8 When 10
binds to DPP-IV, Ser630 reacts with the nitrile group, resulting
in the formation of an O–C bond between the enzyme and
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4.1 Cysteine
By far the most effort has been directed towards targeting non-
catalytic cysteine residues, for example in cysteine proteases
and protein kinases, where selectivity for a particular member
of a protein family can be challenging. The appeal of cysteine is
due in part to its relatively low abundance in proteins, and its
high nucleophilicity. The thiolate form of cysteine has been
shown to be capable of forming covalent bonds with covalent
warheads spanning a wide range of reactivity, with Michael
acceptors being key examples.12 For the reasons described
above, warheads with low reactivity are generally preferred.
KRAS. KRAS is a GTPase involved in the early stage of many
signal transduction pathways, and has been linked to the
development of many types of cancer. The G12C mutant of
KRAS is associated with colorectal and lung cancers.13 Prevent- Fig. 15 X-ray structure revealing the binding mode of ARS-853 (13)
ing the interaction between KRAS and its downstream signalling (shown in green) in KRAS G12C (PDB: 5F2E). The inhibitor is covalently
partners has been suggested as a possible targeting mechanism. bound to Cys12.
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Fig. 16 First generation EGFR inhibitors gefitinib (14) and erlotinib (15).
4.2 Lysine
Since cysteine residues are not always available in a protein
binding site, attempts have also been made to target lysine
residues.20 Lysine is more abundant than cysteine and is a
harder nucleophile, therefore targeting lysine offers alternative
routes to covalent inhibition. The typical pKa of a lysine residue
is 10.4, and therefore most lysine residues will be protonated
Fig. 17 Early covalent inhibitors of EGFR, 2 0 -thioadenosine (16) and PD- under physiological conditions. Surface lysine residues are
168393 (17). more likely to be in the protonated form, but buried lysines
are typically less solvent accessible and may exhibit perturbations
in pKa favouring the neutral form. Only the neutral form is
nucleophilic, and therefore selectivity can potentially be achieved
despite the high abundance of lysine. However, locating lysine
residues with their pKas sufficiently lowered to exist in the neutral
form within a binding site is challenging. One example of such an
approach is through a surface lysine in the myeloid leukemia cell
differentiation protein (Mcl-1) with a reversible covalent aryl
boronic acid carbonyl warhead (19) (Fig. 20).21
Model reactions using N-a-acetyl-lysine and glutathione have
suggested that lysine is less reactive than cysteine towards soft
Fig. 18 Neratinib (18). electrophiles such as acrylamides, but more reactive towards
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Fig. 25 Schematic representation of the terminology used for the location of cysteine residues surrounding the ATP binding pocket across the human
kinome. Based on crystal structure of interleukin-2 tyrosine kinase domain with staurosporine bound (PDB 1SM2). Reprinted with permission from ref. 5.
Copyright 2012 American Chemical Society.
a preference for the former protonation state. However, whether the cysteine is capable of covalent modification.
cysteines located in more polar environments, where nearby As described in Section 6.4, molecular dynamics simulations
positive charge can stabilize the thiolate state of the side chain can be useful in such cases. Conformational sampling can
can display much lower pKa values. For example, the active site indicate the most favourable side chain conformations and their
cysteine in cysteine proteases (which forms an ion pair with relative occupations.
histidine) falls in the region of 2.5–3.5.35 Whilst the thiolate
form is expected to be accessible to a cysteine with a pKa of 5.3 Finding and developing a covalent lead
8.5, a cysteine with a lower pKa value would spend significantly The most commonly used strategies for developing a covalent
more time in the deprotonated form. It is therefore assumed inhibitor are summarized in Fig. 26. The moment at which the
that targeting cysteines with lower pKas will facilitate covalent covalent warhead is added varies from early on (i.e. present in
binding. Experimental determination of cysteine pKa is non- the initial hit), to right at the end of compound optimisation.
trivial, and has been achieved for a relatively small number of The decision of which strategy (or strategies) to select will
proteins. There are a number of computational approaches depend on the amount of prior knowledge and chemical equity
for calculating the pKa of titratable amino acid residues available when embarking on a new project.
(e.g. empirical, Poisson–Boltzmann, thermodynamic integra- Phenotypic or ‘black-box’ screening of covalent inhibitors is
tion, constant-pH molecular dynamics), some of these were the method by which many historic covalent inhibitors were
compared in a study by Rowley et al.36 on protein systems where discovered. In such an approach, compounds are screened
experimental cysteine pKa measurements have been made. against a suitable cellular assay to identify those that cause a
Whilst computational approaches generally do not quantita- desirable change in phenotype. The biological target of such
tively predict pKa values of cysteine, they may be used for molecules may be established after the compounds have been
comparing relative values both between targets and between discovered, although this is not always possible or required.37
cysteines of the same target. The benefits of this method are that it is (a) a direct way to
Assuming that a cysteine is close to the binding pocket and identify an efficacious compound and (b) minimal information
appears to be in a sufficiently polar environment to enable of the target is required. The main drawback of this method is
deprotonation, the side-chain orientation should ideally be that there are relatively few potentially covalent compounds
considered. As it is commonly accepted that reversible binding available in screening collections, as historically more attention
occurs before the covalent bond formation, the target cysteine has been directed towards non-covalent drug development.
side chain should be oriented towards the binding pocket, in Hence, the amount of diversity is typically limited within covalent
order for a covalent bond to form to the inhibitor. X-ray libraries. Additionally, it may be difficult to achieve selectivity for a
structures can be valuable for indicating the average orienta- target without target or structural information available.
tion of amino acid side chains, but do not reveal dynamic Covalent fragment screening may be a useful approach
motion, which is important when considering proteins. Also for where there are no known reversible inhibitors of a target. A
poorly resolved regions, such as those located on flexible loops, selection of low molecular weight covalent compounds is typically
crystal structures may not provide a definitive answer as to screened against a target, with covalent binding confirmed by
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commonly used include mass spectrometry studies, testing molecular dynamics (MD) and Monte Carlo (MC), allow con-
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compounds against cysteine to serine mutants and X-ray formational sampling to be performed on X-ray structures, or
crystallography. docking poses. MD simulations allow the time dependent
motion between different conformational minima to be
explored. A major drawback to performing MD simulations
6. Computer-aided covalent drug using an MM treatment of the atoms, is that such methods are
design not capable of modelling chemical reactivity. Hence the cova-
lent bond formation event cannot be modelled with such an
Molecular modelling is used extensively in drug development, approach.
and can play a part in prioritising compounds for synthesis, MD simulations can be used within a covalent drug design
post-rationalising experimental observations, and providing project to sample the side chain conformations of a binding
atomic level explanations that can be used to guide further site reactive residue, in order to evaluate its accessibility to a
design efforts. Many of the modelling methods used in bound ligand. MD can also be performed on covalent docking
drug design were developed for application to non-covalent poses, to observe whether non-covalent binding interactions
inhibitors, and have been extensively reviewed elsewhere.40 are maintained once the covalent attachment has formed. For
Although most can also be applied to covalent drug design,41 example, an important part of the reversible recognition of
special considerations, or modified software packages, are protein kinase inhibitors arises from hydrogen bonding inter-
sometimes required, in order to account for the covalent bond actions with the kinase hinge region.
formed between ligand and substrate. Here we briefly intro- Free energy perturbation (FEP) methods have become a
duce some molecular modelling techniques that are useful for useful tool in drug design for calculating relative binding
covalent drug design. affinities of novel compounds to protein binding pockets,
allowing potency improvements to be predicted.43 Relative
6.1 Covalent docking
binding free energies of covalent inhibitors have also been
Docking is a valuable tool in structure-based drug design. predicted using FEP.44 At present, covalent FEP depends on
However, conventional docking approaches have limited use MM force fields, and therefore can only predict changes in
for covalent inhibitors, due to the inability to consider the affinity for the reversible binding component of the inhibitor.
covalent bond formation. Steric repulsion between the covalent Hence, the effects of substituents on warhead reactivity
warhead and the reactive residue may prevent relevant docking cannot be modelled. However, FEP is potentially useful for
poses from being identified. Fortunately, several docking optimizing non-covalent recognition during lead optimiza-
programs now have functionality for covalent docking. Provid- tion, particularly for regions distal to the warhead. This can
ing the suitable functional group has been coded into the be especially valuable as the synthesis of covalent inhibitors
docking program, docking poses are located in which the can be challenging.
covalent bond between receptor and ligand has been formed.
A strain penalty can be included to account for deviations from 6.3 Warhead reactivity
the optimal geometry around the covalent bond. Whilst this Often the reactivity of a covalent warhead will not be in an
approach can be used to assess whether a covalent inhibitor can appropriate reactivity range. When this is the case, it may be
be accommodated in a binding pocket, as well as for scoring ligands possible to tune the reactivity by making structural changes
based on potential non-covalent ligand-receptor interactions, it around the warhead, or modify/replace it entirely. For
cannot currently consider the reactivity of the covalent warhead. example, in the case of cysteine-targeting warheads, making
This needs to be considered separately, as described below. the warhead more electrophilic will be expected to increase
When designing covalent libraries for screening campaigns, the reactivity. This can be achieved by the addition of
covalent docking can be used to filter out compounds that are electron-withdrawing substituents on the inhibitor at a posi-
unlikely to fit in the binding pocket of interest. London tion close to the warhead. A commonly used experimental
et al. have used a covalent docking protocol to screen assay for estimating the reactivity of cysteine-targeting
large virtual libraries of electrophilic fragments to identify warheads is measurement of the half-life towards adduct
reversible covalent fragments that target non-conserved formation with glutathione (GSH). However, such GSH assays
cysteine residues in several protein kinases.42 The authors are often relatively low-throughput and require compounds to
reported sub-micromolar active compounds, indicating the be synthesized. Several groups have demonstrated that GSH
potential use of such an approach for the rapid discovery of half-life can be predicted using computational methods.45,46
covalent probe molecules. These methods include Hammett parameters, quantum
mechanical (QM) calculations and pKa predictions. Such
6.2 Molecular mechanics (MM) based simulations methods can be used to rank compounds based on predicted
Whilst X-ray crystal structures are invaluable for structure- reactivity and help to prioritise ‘virtual’ compounds for synth-
based drug design, they may be misleading in terms of esis that fall in the desired range. Understanding substituent
conformational preferences of amino acid side chains. Mole- effects on warhead reactivity therefore enables knowledge-
cular mechanics (MM) based simulation methods, such as driven design of covalent inhibitors.
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