Computational study of binding of epothilone A to β-tubulin.

Understanding the interactions of epothilones with β-tubulin is crucial for computer aided rational design of macrocyclic drugs based on epothilones and epothilone derivatives. Despite numerous structure-activity relationship investigations we still lack substantial knowledge about the binding mode of epothilones and their derivatives to β-tubulin. In this work, we reevaluated the electron crystallography structure of epothilone A/β-tubulin complex (PDB entry 1TVK) and proposed an alternative binding mode of epothilone A to β-tubulin that explains more experimental facts.

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Structure–Activity Relationship of Adenosine 5′-diphosphoribose at the Transient Receptor Potential Melastatin 2 (TRPM2) Channel: Rational Design of Antagonists

Journal of Medicinal Chemistry ◽

10.1021/jm401497a ◽

2013 ◽

Vol 56 (24) ◽

pp. 10079-10102 ◽

Cited By ~ 39

Author(s):

Christelle Moreau ◽

Tanja Kirchberger ◽

Joanna M. Swarbrick ◽

Stephen J. Bartlett ◽

Ralf Fliegert ◽

...

Keyword(s):

Rational Design ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Structure Activity ◽

Transient Receptor Potential Melastatin ◽

Trpm2 Channel ◽

Transient Receptor ◽

Relationship Of

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Structure–Activity Relationship of RGD-Containing Cyclic Octapeptide and αvβ3 Integrin Allows for Rapid Identification of a New Peptide Antagonist

International Journal of Molecular Sciences ◽

10.3390/ijms21093076 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3076 ◽

Cited By ~ 1

Author(s):

Aaron Silva ◽

Wenwu Xiao ◽

Yan Wang ◽

Wei Wang ◽

Heng Wei Chang ◽

...

Keyword(s):

Rational Design ◽

Tumor Imaging ◽

Screening Method ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Sequence Motif ◽

Αvβ3 Integrin ◽

Structure Activity ◽

Cyclic Octapeptide

The αvβ3 integrin, a receptor for many extracellular matrix proteins with RGD-sequence motif, is involved in multiple physiological processes and highly expressed in tumor cells, therefore making it a target for cancer therapy and tumor imaging. Several RGD-containing cyclic octapeptide (named LXW analogs) were screened as αvβ3 antagonists with dramatically different binding affinity, and their structure–activity relationship (SAR) remains elusive. We performed systematic SAR studies and optimized LXW analogs to improve antagonistic potency. The NMR structure of LXW64 was determined and docked to the integrin. Structural comparison and docking studies suggested that the hydrophobicity and aromaticity of the X7 amino acid are highly important for LXW analogs binding to the integrin, a potential hydrophobic pocket on the integrin surface was proposed to play a role in stabilizing the peptide binding. To develop a cost-efficient and fast screening method, computational docking was performed on LXW analogs and compared with in vitro screening. A consistency within the results of both methods was found, leading to the continuous optimization and testing of LXW mutants via in silico screening. Several new LXW analogs were predicted as the integrin antagonists, one of which—LXZ2—was validated by in vitro examination. Our study provides new insight into the RGD recognition specificity and valuable clues for rational design of novel αvβ3 antagonists.

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