Navigation Links
Scripps Research study challenges conventional theory of modern drug design
Date:10/10/2010

JUPITER, Fl, October 7, 2010 Scientists from The Scripps Research Institute have uncovered new evidence that challenges the current theory about a process key to the way modern drugs are designed and how they work in the human body.

The new study was published October 10, 2010 in an advance, online edition of the journal Nature Chemical Biology.

Currently, the theory about ligands compounds that bind to proteins and trigger a specific biological action and how they bind to proteins runs along the lines of a one person-one vote paradigm. Ligands are considered to be the relatively static partner in the process, and easily rejected if the protein dramatically changes shape.

In contrast, working with the molecular systems that recognize the hormone estrogen, the new Scripps Research study found that as protein receptors change shape ligands can adapt to that change, binding productively to both active and inactive structures.

"To our great surprise, the ligand bound differently to the active and inactive conformations of the receptor," said Kendall Nettles, an associate professor in the Department of Cancer Biology at Scripps Florida. "This strongly suggests a novel mechanism for managing [cell] signaling activity. The implications of this are profound, both for our understanding of how ligands regulate protein activity, and as a novel approach in drug discovery."

Changing the Drug Discovery Model

In the current study, the scientists worked with a receptor (which binds substances triggering certain biological effects) for the hormone estrogen and a well known estrogen receptor antagonist (which blocks the receptor). Estrogen receptors are activated by the hormone estrogen, which is one of two primary female sex hormones (the other is progesterone). Disturbances in estrogen levels play a role in number of disorders including cancers, heart disease, and stroke in women.

When ligands bind to a specific subset of receptors, the ligands stabilize specific protein conformations, turning on (or off) molecular switches that control diverse cellular functions. For example, the binding of the breast cancer treatment tamoxifen is specific for the inactive conformation of the estrogen receptor this locks the receptor in place, blocks the active conformation and prevents tumor growth.

"Our new findings suggest that we need to think not only about an ensemble of protein conformations, but also an ensemble of ligand binding orientations when we think about therapeutic compounds," Nettles said. "As the protein and ligand move together, each can have a unique affinity, and activity profile, which working together defines the signaling output."

Nettles is excited by the possibility the new study suggests of working with an ensemble of ligand conformations, perhaps combining one with anti-inflammatory properties which play a role in cancer with another that blocks tumor growth. "This would give you dual therapeutic activity, potentially doubling the effectiveness of the treatment," he said.

Nettles is also eager to find out whether the new study's findings apply to other ligand-protein pairs. "If ligand dynamics turn out to be a general feature of small molecule signaling," he said, "then our findings have the potential to transform how we think about chemical biology."


'/>"/>

Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

Related biology news :

1. Scripps research team solves structure of beneficial virus
2. Scripps research team sheds light on immune system suppression
3. Scripps Florida scientists awarded $1.5M to fight major water and food parasites
4. Scripps research scientists identify compounds for stem-cell production from adult cells
5. Scripps research scientists identify blood component that turns bacteria virulent
6. Scripps research team defines new painkilling chemical pathway
7. Dolphin population stunted by fishing activities, Scripps/NOAA study finds
8. Scripps Research scientists shed light on how DNA is unwound so that its code can be read
9. Scripps scientists develop first examples of RNA that replicates itself indefinitely
10. Scripps scientists create first crystal structure of an intermediate particle in virus assembly
11. Historical photographs expose decline in Floridas reef fish, new Scripps study finds
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:1/27/2016)... WEST CHESTER, Ohio , Jan. 27, 2016 /PRNewswire/ ... services supplier based in West Chester, Ohio ... and their award winning service staff, based in ... Track,s technical capacity and ability to provide modifications, installations ... John Dovalina , CEO of PLUS, commented, "PLUS ...
(Date:1/21/2016)... India , January 21, 2016 ... According to a new market research report "Emotion Detection ... and Others), Software Tools (Facial Expression, Voice Recognition ... Regions - Global forecast to 2020", published by ... is expected to reach USD 22.65 Billion by ...
(Date:1/15/2016)... 2016 Recent publicized breaches in cyber security ... ways to ensure data security and user authentication in ... Android that ties a user,s mobile number ... a hardware authorization token. Customer service agents who employ ... their KodeKey enabled device to verify their identity.  Companies ...
Breaking Biology News(10 mins):
(Date:2/4/2016)... Oakland, California (PRWEB) , ... February 04, 2016 ... ... Artificial Intelligence (AI) and leading supplier of Semantic Graph Database technology has been ... Graph Database Products ” by Corporate America Magazine. , “At Corporate America, it’s ...
(Date:2/3/2016)... SAN DIEGO , Feb. 3, 2016 /PRNewswire/ ... medicine company with the first pluripotent stem cell-derived ... 1 diabetes in clinical-stage development, today announced that ... Janssen Pharmaceutical Companies of Johnson & Johnson, have ... BetaLogics group into ViaCyte.  The agreement provides ViaCyte ...
(Date:2/3/2016)... Denmark , Feb. 3, 2016 Ascendis ... biotechnology company that applies its innovative TransCon technology to ... present at an upcoming investor conference.Event:2016 Leerink Partners Global ... NY Date:  , Wednesday, February 10, 2016 Time:  ... www.ascendispharma.com . --> An audio webcast ...
(Date:2/3/2016)... Denver, Colorado (PRWEB) , ... February 03, 2016 ... ... to hospitals, has established a new office dedicated to the North American healthcare ... provide turnkey solutions to healthcare facilities. The company will provide new pneumatic ...
Breaking Biology Technology: