The finding by scientists at the University of California, Riverside that more flexible molecule bind more tightly to their targets turns the received wisdom about drug design on its head.
Often developers will modify naturally-flexible drug candidates to make them more rigid, thinking that - like a lock and key - this will help them to bind more tightly to disease-associated proteins.
The UC Riverside team - led by graduate student Wanli You - found that in the case of drugs inhibiting a breast cancer drug target BRCT (breast-cancer-gene 1 C-terminal), more flexible molecules were significantly more effective at binding to the target than a "rigidified" structure because they could rearrange themselves after binding.
That is an important result, particularly because drug developers have struggled to develop effective inhibitors of BRCT as well as other so-called 'promiscuous' protein targets which have multiple functions and so have an inherently flexible structure.
BRCT inhibitors are considered to have potential when used to sensitize breast and ovarian cancer cells to DNA-damaging chemotherapy drugs
When molecules bind to their partners they usually decrease their flexibility in a manner described as an 'entropic penalty' - in other words a decrease in the randomness of a molecule that equates to an increase in rigidity.
Having a large entropy penalty has been shown to be bad for creating a tight binding, so drug developers try to reduce this entropy cost when designing ligands that bind to molecular targets. That is an effective strategy for many targets - but less so for promiscuous proteins and for blocking some protein-protein interactions, they report in the journal PLoS Computational Biology.
The principles could be applied in drug development targeting other diseases and also in basic cell biology studies.
Commenting on the finding, one of the authors of the paper, Chia-en Chang who is associate professor of chemistry at UC Riverside and a member of its Institute for Integrative Genome Biology said: "This was really unexpected and opens up a new direction for designing pharmaceutical drugs."