scholarly journals Rational Design, Structure–Activity Relationship, and Immunogenicity of Hypoallergenic Pru p 3 Variants

2019 ◽  
Vol 63 (18) ◽  
pp. 1900336 ◽  
Author(s):  
Stephanie Eichhorn ◽  
Angelika Hörschläger ◽  
Markus Steiner ◽  
Josef Laimer ◽  
Bettina M Jensen ◽  
...  
Keyword(s):  
Rational Design ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Design Structure ◽  
Pru P 3

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

2020 ◽  
Vol 21 (9) ◽  
pp. 3076 ◽  
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.

Design, Structure–Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990

2014 ◽  
Vol 57 (21) ◽  
pp. 9124-9129 ◽  
Author(s):  
Christopher M. McBride ◽  
Barry Levine ◽  
Yi Xia ◽  
Cornelia Bellamacina ◽  
Timothy Machajewski ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Design Structure ◽  
In Vivo Characterization

scholarly journals Rational Design of Novel Anti-microtubule Agent (9-Azido-Noscapine) from Quantitative Structure Activity Relationship (QSAR) Evaluation of Noscapinoids

2011 ◽  
Vol 16 (9) ◽  
pp. 1047-1058 ◽  
Author(s):  
Seneha Santoshi ◽  
Pradeep K. Naik ◽  
Harish C. Joshi
Keyword(s):  
Rational Design ◽  
Lymphoblastic Leukemia ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Nuclear Magnetic Resonance Analysis ◽  
Quantitative Structure ◽  
Structural Framework ◽  
Structure Activity

An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran-1(3H)-one], was discovered in the authors’ laboratory as a novel type of tubulin-binding agent that mitigates polymerization dynamics of microtubule polymers without changing overall subunit-polymer equilibrium. To obtain systematic insight into the relationship between the structural framework of noscapine scaffold and its antitumor activity, the authors synthesized strategic derivatives (including two new ones in this article). The IC50 values of these analogs vary from 1.2 to 56.0 µM in human acute lymphoblastic leukemia cells (CEM). Geometrical optimization was performed using semiempirical quantum chemical calculations at the 3-21G* level. Structures were in agreement with nuclear magnetic resonance analysis of molecular flexibility in solution and crystal structures. A genetic function approximation algorithm of variable selection was used to generate the quantitative structure activity relationship (QSAR) model. The robustness of the QSAR model ( R2 = 0.942) was analyzed by values of the internal cross-validated regression coefficient ( R2LOO = 0.815) for the training set and determination coefficient ( R2test = 0.817) for the test set. Validation was achieved by rational design of further novel and potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine. The experimentally determined value of pIC50 for both the compounds (5.585 M) turned out to be very close to predicted pIC50 (5.731 and 5.710 M).

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