Molecular flexibility shown to help pharmaceutical drugs bind to their targets

August 25, 2016

Scientists have discovered an alternative way to create a stronger binding between pharmaceutical drugs and the part of the body they are targeting - a development that can be used to fight a variety of diseases, including breast cancer. The study published in PLOS Computational Biology shows that flexible molecules, instead of rigid ones, as previously thought, can bind more effectively to the proteins causing the disease.

Being a tight binder is important for a molecule to be a good pharmaceutical drug. When designing a pharmaceutical drug, scientists typically make molecules - which are naturally flexible - rigid so that they can strongly bind, like a lock and key, with the disease causing protein in the body.

When molecules bind to their partners they usually decrease their flexibility which leads to the so-called entropy penalty. Having a large entropy penalty has been shown to be bad for creating a tight bindings. Scientists aim to reduce it so that the drug can stay on the target protein and alter its functional behavior for good. However, one key problem to this approach is that scientists are reaching the limit of how much rigidity can be produced in order to reduce entropy penalty and result in tighter binders.

Researchers, led by Wanli You (University of California), found that keeping the molecules flexible, as opposed to making them rigid, both reduced the entropy penalty and created a stronger binding. One of the authors, Chia-en A. Chang, notes that "This was really unexpected and opens up a new direction for designing pharmaceutical drugs".

In order to discover this, the researchers examined the thermodynamic properties of different ligands binding to a promiscuous modular protein, Breast-cancer-gene 1 (BRCA1) C-terminal (BRCT). The authors used molecular dynamics simulations and a rigorous free energy calculation method to study ligands binding to BRCT, understand promiscuous molecular recognition and guide inhibitor design. Flexible ligands, the researchers found, may utilize multiple conformations in their bound states to keep good attractions with BRCT whilst also reducing entropy cost.

The research focused on breast cancer drugs, but the principles could be applied in drug development targeting other diseases and also in basic cell biology studies.
-end-
In your coverage please use this URL to provide access to the freely available article in PLOS Computational Biology: http://dx.plos.org/10.1371/journal.pcbi.1005057

Contact: Name: Chia-en A. Chang
Email: chiaenc@ucr.edu

Citation: You W, Huang Y-mM, Kizhake S, Natarajan A, Chang C-eA (2016) Characterization of Promiscuous Binding of Phosphor Ligands to Breast-Cancer-Gene 1 (BRCA1) C-Terminal (BRCT): Molecular Dynamics, Free Energy, Entropy and Inhibitor Design. PLoS Comput Biol 12(8): e1005057. doi:10.1371/journal.pcbi.1005057

Image Caption: Molecular flexibility Shown to Help Pharmaceutical Drugs Bind to Their Targets

Image Credit: Fabio Hofnik / Flickr

Image Link: http://blogs.plos.org/everyone/files/2016/08/Chang-striking-image.jpg

Funding: This research was supported by the US National Institutes of Health (GM109045) http://www.nih.gov/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

About PLOS Computational Biology

PLOS Computational Biology features works of exceptional significance that further our understanding of living systems at all scales through the application of computational methods. For more information follow @PLOSCompBiol on Twitter or contact ploscompbiol@plos.org.

PLOS

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.