Molecular flexibility found useful with pharmaceutical drugs to treat varying diseases

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The PLOS Computational Biology Journal has published a new discovery made by Scientists at the University of California, U.S.A through the postulation of option to invent a stronger binding between pharmaceutical drugs and the targeted part of the body. This development is found useful in fighting a number of diseases which is not limited to breast cancer.

In designing a pharmaceutical drug, scientists usually transform molecules from its naturally flexible form to a rigid substance that can easily bind strongly with the disease causing protein in the body.

The team aimed to reduce a condition known as entropy penalty so as to enable the drug to stay on the target protein and disrupt 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.
Wanli You discovered that leaving the molecules flexible, as against transforming them into rigid form both reduced the entropy penalty and established a stronger binding.

According to another author, Chia-en A. Chang, opines that the situation was really unexpected and opens up a new direction for designing pharmaceutical drugs. To uncover this, the team examined the thermodynamic properties of different ligands binding to a promiscuous modular protein, Breast-cancer-gene 1 (BRCA1) C-terminal (BRCT) and used the molecular dynamics simulations as well as a rigorous free energy calculation method to study ligands binding to BRCT, understand promiscuous molecular recognition and guide inhibitor design. Flexible ligands were found by the researchers, to utilize multiple conformations in their bound states to keep good attractions with BRCT whilst also reducing entropy cost.

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Although, the study focused on breast cancer drugs, the principles are not inapplicable in the development of drug aimed at managing other diseases generally and it basic cell biology studies in particular.






Article Source
Characterization of Promiscuous Binding of Phosphor Ligands to Breast-CancerGene 1 (BRCA1) C-Terminal (BRCT): Molecular Dynamics, Free Energy, Entropy and Inhibitor Design, You W, Huang Y-mM, Kizhake S, Natarajan A, Chang C-eA, PLOS Computational Biology, doi:10.1371/journal.pcbi.1005057, published online 11 August 2016.

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