Abstract:
:Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (ΔG(off)≠). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development.
journal_name
Proc Natl Acad Sci U S Aauthors
Bai F,Xu Y,Chen J,Liu Q,Gu J,Wang X,Ma J,Li H,Onuchic JN,Jiang Hdoi
10.1073/pnas.1301814110subject
Has Abstractpub_date
2013-03-12 00:00:00pages
4273-8issue
11eissn
0027-8424issn
1091-6490pii
1301814110journal_volume
110pub_type
杂志文章abstract::Complexin activates Ca(2+)-triggered neurotransmitter release and regulates spontaneous release in the presynaptic terminal by cooperating with the neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and the Ca(2+)-sensor synaptotagmin. The N-terminal domain of complexin is importa...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1604348113
更新日期:2016-08-09 00:00:00
abstract::The self-association of gene-32 protein has been studied by sedimentation equilibrium centrifugation and polyacrylamide gel electrophoresis, in order to better understand its role in DNA replication and genetic recombination. The monomer molecular weight of gene-32 protein is 38,000 in guanidine hydrochloride and 34,0...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.9.2741
更新日期:1972-09-01 00:00:00
abstract::The effect of carlorie intake on the development of spontaneous mammary tumors in virgin C3H mice was studied. Only about 10% of the mice fed a low-calorie diet [10 kcal/day (1 kcal = 4.184 kJ)] since weaning developed mammary tumors, compared to about 60% of those mice that were reared on high-calorie diets (16 kcal/...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.79.24.7758
更新日期:1982-12-01 00:00:00
abstract::Pleistocene residential sites with multiple contemporaneous human burials are extremely rare in the Americas. We report mitochondrial genomic variation in the first multiple mitochondrial genomes from a single prehistoric population: two infant burials (USR1 and USR2) from a common interment at the Upward Sun River Si...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 历史文章,杂志文章
doi:10.1073/pnas.1511903112
更新日期:2015-11-10 00:00:00
abstract::The fluorescence of the supposedly buried tryptophan in ribonuclease T1 has been found to be collisionally quenched by acrylamide with a rate constant of 3 X 10(8) M--1 sec--1. Only a slight decrease in the quenching rate is observed upon a 5-fold increase in the viscosity of the solution. For this to be the case, the...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.72.9.3290
更新日期:1975-09-01 00:00:00
abstract::Mechanical robustness of the cell under different modes of stress and deformation is essential to its survival and function. Under tension, mechanical rigidity is provided by the cytoskeletal network; with increasing stress, this network stiffens, providing increased resistance to deformation. However, a cell must als...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0901462106
更新日期:2009-06-30 00:00:00
abstract::13C-labeled precorrin-6x is biosynthesized by cell-free protein preparations from Pseudomonas denitrificans in separate experiments using delta-amino[5-13C]levulinic acid and the corresponding delta-amino[4-13C]- and delta-amino[3-13C]levulinic acid-labeled forms in conjunction with S-[methyl-13C]adenosylmethionine fo...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.87.22.8800
更新日期:1990-11-01 00:00:00
abstract::Trial electron density functions have some conceptual and computational advantages over wave functions. The properties of some simple density functions for H(+) (2) and H(2) are examined. It appears that for a diatomic molecule a good density function would be given by rho = N(A(2) + B(2)), in which A and B are short ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.77.4.1725
更新日期:1980-04-01 00:00:00
abstract::Phycobilisomes isolated from eight different species of cyanobacteria contain in addition to the light-harvesting phycobiliproteins, a small number of colorless polypeptides with molecular weights higher than those of the chromopolypeptide subunits of the phycobiliproteins. In the phycobilisomes of the species examin...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.74.4.1635
更新日期:1977-04-01 00:00:00
abstract::The tumor promoter phorbol 12-myristate 13-acetate (PMA) induces characteristic reversible changes of cell shape in certain fibroblastic lines: motile lamellas are transformed into noncontractile narrow processes; simultaneously, the actin microfilament network of lamellas is locally disorganized. This reaction to PMA...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.87.5.1884
更新日期:1990-03-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2012-05-29 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0408940102
更新日期:2005-03-08 00:00:00
abstract::Several polypeptides contained in the coat and the core of adenovirus type 2 particles have been identified as virus gene products. They are synthesized in vitro by a cell-free protein-making system programmed by adenovirus type 2 messenger RNA that has been hybridized with and eluted from virus DNA. Fractionation by ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.71.9.3385
更新日期:1974-09-01 00:00:00
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更新日期:2013-01-29 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.97.6.2431
更新日期:2000-03-14 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.73.6.2128
更新日期:1976-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2012-11-27 00:00:00
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更新日期:1994-10-11 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2010-11-30 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2008-07-15 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2007-01-16 00:00:00
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pub_type: 杂志文章
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更新日期:1991-10-01 00:00:00