한빛사 논문
Reed M. Stein1,11, Hye Jin Kang2,11, John D. McCorvy2,9,11, Grant C. Glatfelter3,10,11, Anthony J. Jones3, Tao Che2, Samuel Slocum2, Xi-Ping Huang2, Olena Savych4, Yurii S. Moroz5,6, Benjamin Stauch7,8, Linda C. Johansson7,8, Vadim Cherezov7,8, Terry Kenakin2, John J. Irwin1, Brian K. Shoichet1,*, Bryan L. Roth2,* & Margarita L. Dubocovich3,*
1 Department of Pharmaceutical Chemistry, University of California, San Francisco, California, 94158, USA. 2 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, 27599-7365, USA. 3 Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York, 14203, USA. 4 Enamine Ltd, Chervonotkatska Street78, Kyiv, 02094, Ukraine. 5 National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv, 01601, Ukraine. 6 Chemspace, 7Deer Park Drive, Suite M-5, Monmouth Junction, NJ, 08852, USA. 7 Bridge Institute, USC Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, California, 90089, USA. 8 Department of Chemistry, University of Southern California, Los Angeles, California, 90089, USA. 9 Present address: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA. 10 Present address: Designer Drug Research Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, 21224, USA. 11 These authors contributed equally: Reed M. Stein, Hye Jin Kang,John D. McCorvy, Grant C. Glatfelter.
*Correspondence to Brian K. Shoichet or Bryan L. Roth or Margarita L. Dubocovich
Abstract
The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions via actions at two G protein-coupled receptors: MT 1 and MT 2. Circadian release of high nighttime levels of melatonin from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing physiology and behavior to the light-dark cycle 1–4. The two receptors are established drug targets for aligning circadian phase in disorders of sleep 5,6 and depression 7,1–4,8,9. Despite their importance, few if any in vivo active MT 1 selective ligands have been reported 2,8,10–12, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked over 150 million virtual molecules against an MT1 crystal structure, prioritizing structural fit and chemical novelty. Thirty-eight high-ranking molecules were synthesized and tested, revealing ligands in the 470 pM to 6 μM range. Structure-based optimization led to two selective MT1 inverse agonists, topologically unrelated to previously explored chemotypes, that were tested in mouse models of circadian behavior. Unexpectedly, the MT 1-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 hrs when given at subjective dusk, an agonist-like effect eliminated in MT 1- but not in MT 2-knockout mice. This study illustrates opportunities for modulating melatonin receptor biology via MT 1-selective ligands, and for the discovery of new, in vivo-active chemotypes from structure-based screens of diverse, ultra-large libraries.
논문정보
관련 링크
연구자 키워드
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기