Chemical proteomics-based drug design: target and antitarget fishing with a catechol-rhodanine privileged scaffold for NAD(P)(H) binding proteins.
Drugs typically exert their desired and undesired biological effects by virtue of binding interactions with protein target(s) and antitarget(s), respectively. Strategies are therefore needed to efficiently manipulate and monitor cross-target binding profiles (e.g., imatinib and isoniazid) as an integrated part of the drug design process. Herein we present such a strategy, which reverses the target --> lead rational drug design paradigm. Enabling this approach is a catechol-rhodanine privileged scaffold for dehydrogenases, which is easily tuned for affinity and specificity toward desired targets. This scaffold crosses bacterial (E. coli) cell walls, and proteome-wide studies demonstrate it does indeed bind to and identify NAD(P)(H)-binding proteins that are potential drug targets in Mycobacterium tuberculosis and antitargets (or targets) in human liver. This approach to drug discovery addresses key difficulties earlier in the process by only pursuing targets for which a chemical lead and optimization strategy are available, to permit rapid tuning of target/antitarget binding profiles.
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Xia
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Department of Chemistry, Chemical Proteomics Facility at Marquette, Marquette University, PO Box 1881, Milwaukee, Wisconsin 53201, USA.
Wakim
Bassam
B
Sem
Daniel S
DS
D002396:Catechols / Q000737:chemistry*; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry; D015394:Molecular Structure; D009249:NADP / Q000737:chemistry* / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D040901:Proteomics; D012236:Rhodanine / Q000737:chemistry*; D012685:Sepharose / Q000031:analogs & derivatives / Q000737:chemistry
D002396:Catechols; D011506:Proteins; D009249:NADP; C024903:aminohexyl-sepharose; D012236:Rhodanine; D012685:Sepharose; C034221:catechol