Conservation of Potentially Druggable Cavities in
Intrinsically Disordered Proteins
Posted on 2018-11-16 - 14:34
Intrinsically disordered
proteins (IDPs) exist in highly dynamic
conformational ensembles, which pose a major obstacle for drug development
targeting IDPs because traditional rational drug design relies on
unique three-dimensional structures. Here, we analyzed the conservation
(especially structural conservation) of potentially druggable cavities
in 22 ensembles of IDPs. It was found that there is considerable conservation
for potentially druggable cavities within each ensemble. The average
common atom percentage of potentially druggable cavities is as high
as 54%. The average root-mean-squared deviation of common atoms ranges
between 1 and 8 Å for multichain IDPs, and a common pocket is
kept after direct alignment of cavities. In addition, the conservation
of potentially druggable cavities varies among different proteins.
In the comparison of multi- and single-chain IDPs, some multichain
IDPs have an extremely high conservation, whereas another multichain
IDPs’ conservation appears worse, and the single-chain IDPs
have relatively moderate conservations. This study is a new attempt
to generally assess the potentially druggable cavities in IDPs for
taking IDPs as druggable targets, and this work also lends support
to the opinion of IDPs tending to bind to “multiconformational
affinity” compounds.
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Chong, Bin; Li, Maodong; Li, Tong; Yu, Miao; Zhang, Yugang; Liu, Zhirong (2018). Conservation of Potentially Druggable Cavities in
Intrinsically Disordered Proteins. ACS Publications. Collection. https://doi.org/10.1021/acsomega.8b02092
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AUTHORS (6)
BC
Bin Chong
ML
Maodong Li
TL
Tong Li
MY
Miao Yu
YZ
Yugang Zhang
ZL
Zhirong Liu