The Rational Design of Anticancer Platinum Complexes: The Importance of the Structure-Activity Relationship

2009 ◽  
Vol 16 (18) ◽  
pp. 2235-2260 ◽  
Author(s):  
Angel Montana ◽  
Consuelo Batalla
Keyword(s):  
Rational Design ◽  
Platinum Complexes ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity

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.

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 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).

scholarly journals Activities and Conformational Fitting of 1,4-Naphthoquinone Derivatives and Other Cyclic 1,4-Diones Tested In Vitro against Pneumocystis carinii

2001 ◽  
Vol 45 (5) ◽  
pp. 1473-1479 ◽  
Author(s):  
M. D. Ball ◽  
M. S. Bartlett ◽  
M. Shaw ◽  
J. W. Smith ◽  
M. Nasr ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Rational Design ◽  
Chemotherapeutic Agent ◽  
Pneumocystis Carinii ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Immunocompromised Patients ◽  
Structure Activity ◽  
Computer Based

ABSTRACT Atovaquone is a chemotherapeutic agent used to treat pneumonia caused by Pneumocystis carinii in some immunocompromised patients. A set of cyclic 1,4-diones were tested in vitro for ability to inhibit growth of P. carinii, including 22 variously substituted 1,4-naphthoquinones, one bis-1,4-naphthoquinone, and three other quinones. For comparison, the antipneumocystic primaquine and its 5-hydroxy-6-desmethyl metabolite were also tested. At 1.0 μg/ml, seven compounds inhibited growth by at least 39%, with atovaquone at 92%; of these seven, five are 2-hydroxy-1,4-naphthoquinones, while one is a 2-chloro- and another is a 2-methyl-1,4-naphthoquinone. At 0.1 μg/ml, however, the most active compound tested was the primaquine metabolite, which inhibited growth by more than 42% at this concentration. To ascertain a structure-activity relationship, all 1,4-naphthoquinones were compared conformationally by means of computer-based molecular modeling (Spartan) incorporating the Sybyl force field. Without exception, for all 21 monomers tested, the substituent at position 3 of the 1,4-naphthoquinone favored activity most strongly when it simultaneously occupied (i) space centered at about 3 Å from position 3, without projecting steric bulk from the area encompassed by atovaquone's cyclohexyl ring, and (ii) roughly planar space at about 7.3 Å from position 3, without projecting steric bulk perpendicularly. This structure-activity relationship may prove useful in the rational design of better antipneumocystis agents.

Sign in / Sign up

Export Citation Format

Share Document