Subtle structural changes in tetrahydroquinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions.
Tetrahydroquinolines (THQs), a new class of nonsteroidal selective androgen receptor (AR) modulators, have two indispensable functional groups, that is, 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.
Central Research Laboratories, Kaken Pharmaceutical Co., Ltd, 14, Shinomiya Minamikawara-cho, Yamashina, Kyoto 607-8042, Japan. nagata_naoya@kaken.co.jp
Naoya
N
Nagata
Kentaro
K
Kawai
Isao
I
Nakanishi
D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000728:Androgens / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics
D059002:Androgen Receptor Antagonists; D000728:Androgens; D011804:Quinolines; D011944:Receptors, Androgen; C542964:1,2,3,4-tetrahydroquinoline