Abstract
Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine – the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.
| Original language | English |
|---|---|
| Pages (from-to) | 2066-2074 |
| Number of pages | 9 |
| Journal | Bioorganic & Medicinal Chemistry |
| Volume | 27 |
| Issue number | 10 |
| Early online date | 3 Apr 2019 |
| DOIs | |
| Publication status | Published - 15 May 2019 |
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Keywords
- Covalent drug
- Reactivity
- Warhead
Cite this
}
Characterising Covalent Warhead Reactivity. / Martin, James; Mackenzie, Claire; Fletcher, Daniel; Gilbert, Ian (Lead / Corresponding author).
In: Bioorganic & Medicinal Chemistry, Vol. 27, No. 10, 15.05.2019, p. 2066-2074.Research output: Contribution to journal › Article
TY - JOUR
T1 - Characterising Covalent Warhead Reactivity
AU - Martin, James
AU - Mackenzie, Claire
AU - Fletcher, Daniel
AU - Gilbert, Ian
N1 - We would like to acknowledge the University of Dundee for the award of the Nichol-Lindsay PhD studentship (JM), Medicines for Malaria Venture (MMV) for funding, and the Wellcome Trust for funding for the Wellcome Centre for Anti-Infectives Research (203134/Z/16/Z).
PY - 2019/5/15
Y1 - 2019/5/15
N2 - Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine – the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.
AB - Many drugs currently used are covalent inhibitors and irreversibly inhibit their targets. Most of these were discovered through serendipity. Covalent inhibitions can have many advantages from a pharmacokinetic perspective. However, until recently most organisations have shied away from covalent compound design due to fears of non-specific inhibition of off-target proteins leading to toxicity risks. However, there has been a renewed interest in covalent modifiers as potential drugs, as it possible to get highly selective compounds. It is therefore important to know how reactive a warhead is and to be able to select the least reactive warhead possible to avoid toxicity. A robust NMR based assay was developed and used to measure the reactivity of a variety of covalent warheads against serine and cysteine – the two most common targets for covalent drugs. A selection of these warheads also had their reactivity measured against threonine, tyrosine, lysine, histidine and arginine to better understand our ability to target non-traditional residues. The reactivity was also measured at various pHs to assess what effect the environment in the active site would have on these reactions. The reactivity of a covalent modifier was found to be very dependent on the amino acid residue.
KW - Covalent drug
KW - Reactivity
KW - Warhead
UR - http://www.scopus.com/inward/record.url?scp=85064006485&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2019.04.002
DO - 10.1016/j.bmc.2019.04.002
M3 - Article
C2 - 30975501
VL - 27
SP - 2066
EP - 2074
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 10
ER -