Document Detail

Subtle structural changes in tetrahydroquinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions.
MedLine Citation:
PMID:  22794275     Owner:  NLM     Status:  Publisher    
Tetrahydroquinolines (THQs), a new class of nonsteroidal selective androgen receptor (AR) modulators, have two indispensable functional groups, i.e., a hydroxyl group for AR binding and a nitro group for agonistic activity. Interestingly, switching the nitro to a cyano group, the compound acts as an antagonist. To understand this phenomenon, molecular dynamics simulations were applied for dihydrotestosterone (DHT) and representative THQs complexes with AR. Upon ligand binding, the hydroxyl group formed a tight hydrogen-bond (H-bond) with Asn705 on Helix 3 (H3). The immobilization of Asn705 on H3 is helpful in the formation of tight H-bonds with Asp890 on loop 11-12, and this immobilization consequently leads to a stabilization of H12. The difference in the DHT carbonyl isosteres affected the presence or absence of the H-bonds between the hydroxyl group of THQ and Thr877 and the distortion of H12, which is caused by the methyl group of THQ. Thus, the binding, agonist, and antagonist functions were controlled by subtle structural changes in THQ.
Naoya Nagata; Kentaro Kawai; Isao Nakanishi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-13
Journal Detail:
Title:  Journal of chemical information and modeling     Volume:  -     ISSN:  1549-960X     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101230060     Medline TA:  J Chem Inf Model     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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