TY - JOUR
T1 - Are the Apo Proteins Suitable for the Rational Discovery of Allosteric Drugs?
AU - An, Xiaoli
AU - Lu, Shaoyong
AU - Song, Kun
AU - Shen, Qiancheng
AU - Huang, Meilan
AU - Yao, Xiaojun
AU - Liu, Huanxiang
AU - Zhang, Jian
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/1/28
Y1 - 2019/1/28
N2 - Allosteric modulators, by targeting the less-conserved allosteric sites, represent an innovative strategy in drug discovery. These modulators have a distinctive advantage over orthosteric ligands that attach to the conserved, functional orthosteric sites. However, in structure-based drug design, it remains unclear whether allosteric protein structures determined without orthosteric ligand binding are suitable for allosteric drug screening. In this study, we performed large-scale conformational samplings of six representative allosteric proteins uncomplexed (apo) and complexed (holo) with orthosteric ligands to explore the effect of orthosteric site binding on the conformational dynamics of allosteric sites. The results, coupled with the redocking evaluation of allosteric modulators to their apo and holo proteins using their MD trajectories, indicated that orthosteric site binding had an effect on the dynamics of the allosteric sites and allosteric modulators preferentially bound to their holo proteins. According to the analysis data, we constructed a new correlation model for quantifying the allosteric site change driven by substrate binding to the orthosteric site. These results highlight the strong demand to select holo allosteric proteins as initial inputs in structure-based allosteric drug screening when the distance between orthosteric and allosteric sites in the protein is below 5 Å, which is expected to contribute to allosteric drug discovery.
AB - Allosteric modulators, by targeting the less-conserved allosteric sites, represent an innovative strategy in drug discovery. These modulators have a distinctive advantage over orthosteric ligands that attach to the conserved, functional orthosteric sites. However, in structure-based drug design, it remains unclear whether allosteric protein structures determined without orthosteric ligand binding are suitable for allosteric drug screening. In this study, we performed large-scale conformational samplings of six representative allosteric proteins uncomplexed (apo) and complexed (holo) with orthosteric ligands to explore the effect of orthosteric site binding on the conformational dynamics of allosteric sites. The results, coupled with the redocking evaluation of allosteric modulators to their apo and holo proteins using their MD trajectories, indicated that orthosteric site binding had an effect on the dynamics of the allosteric sites and allosteric modulators preferentially bound to their holo proteins. According to the analysis data, we constructed a new correlation model for quantifying the allosteric site change driven by substrate binding to the orthosteric site. These results highlight the strong demand to select holo allosteric proteins as initial inputs in structure-based allosteric drug screening when the distance between orthosteric and allosteric sites in the protein is below 5 Å, which is expected to contribute to allosteric drug discovery.
UR - http://www.scopus.com/inward/record.url?scp=85060633193&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.8b00735
DO - 10.1021/acs.jcim.8b00735
M3 - Article
C2 - 30525607
AN - SCOPUS:85060633193
SN - 1549-9596
VL - 59
SP - 597
EP - 604
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 1
ER -