Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery
The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an 'allele specific' manner. For the medicinal chemist, the structure-guided design of cysteine- reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteinemodifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues..
Medienart: |
Artikel |
---|
Erscheinungsjahr: |
2017 |
---|---|
Erschienen: |
2017 |
Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
---|---|
Enthalten in: |
Current topics in medicinal chemistry - 17(2017), 1, Seite 4-15 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Kenneth K. Hallenbeck [VerfasserIn] |
---|
Links: |
---|
BKL: |
---|
Förderinstitution / Projekttitel: |
|
---|
PPN (Katalog-ID): |
OLC1989810004 |
---|
LEADER | 01000caa a2200265 4500 | ||
---|---|---|---|
001 | OLC1989810004 | ||
003 | DE-627 | ||
005 | 20230515132331.0 | ||
007 | tu | ||
008 | 170207s2017 xx ||||| 00| ||eng c | ||
028 | 5 | 2 | |a PQ20170206 |
035 | |a (DE-627)OLC1989810004 | ||
035 | |a (DE-599)GBVOLC1989810004 | ||
035 | |a (PRQ)benthamscience_primary_http_www_eurekaselect_com_openurl_content_php_genre_article_issn_1568_0266_volume_17_issue_1_spage_40 | ||
035 | |a (KEY)0446467220170000017000100004targetingnoncatalyticcysteineresiduesthroughstruct | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
082 | 0 | 4 | |a 540 |q DNB |
084 | |a PHARM |2 fid | ||
084 | |a 44.40 |2 bkl | ||
100 | 0 | |a Kenneth K. Hallenbeck |e verfasserin |4 aut | |
245 | 1 | 0 | |a Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery |
264 | 1 | |c 2017 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
338 | |a Band |b nc |2 rdacarrier | ||
520 | |a The targeting of non-catalytic cysteine residues with small molecules is drawing increased attention from drug discovery scientists and chemical biologists. From a biological perspective, genomic and proteomic studies have revealed the presence of cysteine mutations in several oncogenic proteins, suggesting both a functional role for these residues and also a strategy for targeting them in an 'allele specific' manner. For the medicinal chemist, the structure-guided design of cysteine- reactive molecules is an appealing strategy to realize improved selectivity and pharmacodynamic properties in drug leads. Finally, for chemical biologists, the modification of cysteine residues provides a unique means to probe protein structure and allosteric regulation. Here, we review three applications of cysteinemodifying small molecules: 1) the optimization of existing drug leads, 2) the discovery of new lead compounds, and 3) the use of cysteine-reactive molecules as probes of protein dynamics. In each case, structure-guided design plays a key role in determining which cysteine residue(s) to target and in designing compounds with the proper geometry to enable both covalent interaction with the targeted cysteine and productive non-covalent interactions with nearby protein residues. | ||
700 | 0 | |a David M. Turner |4 oth | |
700 | 0 | |a Adam R. Renslo |4 oth | |
700 | 0 | |a Michelle R. Arkin |4 oth | |
773 | 0 | 8 | |i Enthalten in |t Current topics in medicinal chemistry |d Hilversum [u.a.] : Bentham Science Publ., 2001 |g 17(2017), 1, Seite 4-15 |w (DE-627)338770283 |w (DE-600)2064823-6 |w (DE-576)435515160 |x 1568-0266 |7 nnns |
773 | 1 | 8 | |g volume:17 |g year:2017 |g number:1 |g pages:4-15 |
856 | 4 | 2 | |u http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1568-0266&volume=17&issue=1&spage=4 |
912 | |a GBV_USEFLAG_A | ||
912 | |a SYSFLAG_A | ||
912 | |a GBV_OLC | ||
912 | |a FID-PHARM | ||
912 | |a SSG-OLC-PHA | ||
912 | |a SSG-OLC-DE-84 | ||
912 | |a SSG-OPC-PHA | ||
912 | |a GBV_ILN_4219 | ||
936 | b | k | |a 44.40 |q AVZ |
951 | |a AR | ||
952 | |d 17 |j 2017 |e 1 |h 4-15 |