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In silico discovery of novel retinoic acid receptor agonist structures.

Schapira M, Raaka BM, Samuels HH, Abagyan R - BMC Struct. Biol. (2001)

Bottom Line: Thirty ligand candidates were tested in vitro.Two novel agonists resulting from the predicted receptor model were active at 50 nM.One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Structural Biology, Skirball Institute of Biomolecular Medicine, New York, USA. schapira@saturn.med.nyu.edu

ABSTRACT

Background: Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia.

Results: We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually) to the structure of the receptor with the Internal Coordinates Mechanics (ICM) program. Thirty ligand candidates were tested in vitro.

Conclusions: Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

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Related in: MedlinePlus

Structure of the novel RAR agonists. Agonists 1 and 2 are shown (respectively A and B). Left: chemical structure of the compounds. Right: Representation of the compounds docked into the binding pocket of RAR (important residues are displayed as sticks: R274, R278, S289), and superimposed with the crystal structure of all-trans RA (green). The receptor is represented as a white ribbon. Hydrogens are not displayed for clarity. Color coding: carbons, oxygens, nitrogens, sulfurs, fluorides and hydrogens are colored white, red, blue, yellow, magenta and gray respectively.
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Figure 5: Structure of the novel RAR agonists. Agonists 1 and 2 are shown (respectively A and B). Left: chemical structure of the compounds. Right: Representation of the compounds docked into the binding pocket of RAR (important residues are displayed as sticks: R274, R278, S289), and superimposed with the crystal structure of all-trans RA (green). The receptor is represented as a white ribbon. Hydrogens are not displayed for clarity. Color coding: carbons, oxygens, nitrogens, sulfurs, fluorides and hydrogens are colored white, red, blue, yellow, magenta and gray respectively.

Mentions: The predicted structure of the complex generated by the virtual screening approach, and further optimized with flexible receptor side-chains details clearly the interactions between the receptor and the ligands (Fig. 5). Agonist 1 and 2 both have a carboxylate group which superimposes with the carboxylate of all-trans RA, and makes stabilizing hydrogen bonds with Arg 274 and 278, and the backbone nitrogen of Ser 289 (Fig. 5). All other receptor/ligand interactions are hydrophobic. As a result, the size and flexibility of the ligand as well as the shape complementarity with the receptor are critical for affinity and specificity.


In silico discovery of novel retinoic acid receptor agonist structures.

Schapira M, Raaka BM, Samuels HH, Abagyan R - BMC Struct. Biol. (2001)

Structure of the novel RAR agonists. Agonists 1 and 2 are shown (respectively A and B). Left: chemical structure of the compounds. Right: Representation of the compounds docked into the binding pocket of RAR (important residues are displayed as sticks: R274, R278, S289), and superimposed with the crystal structure of all-trans RA (green). The receptor is represented as a white ribbon. Hydrogens are not displayed for clarity. Color coding: carbons, oxygens, nitrogens, sulfurs, fluorides and hydrogens are colored white, red, blue, yellow, magenta and gray respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC32304&req=5

Figure 5: Structure of the novel RAR agonists. Agonists 1 and 2 are shown (respectively A and B). Left: chemical structure of the compounds. Right: Representation of the compounds docked into the binding pocket of RAR (important residues are displayed as sticks: R274, R278, S289), and superimposed with the crystal structure of all-trans RA (green). The receptor is represented as a white ribbon. Hydrogens are not displayed for clarity. Color coding: carbons, oxygens, nitrogens, sulfurs, fluorides and hydrogens are colored white, red, blue, yellow, magenta and gray respectively.
Mentions: The predicted structure of the complex generated by the virtual screening approach, and further optimized with flexible receptor side-chains details clearly the interactions between the receptor and the ligands (Fig. 5). Agonist 1 and 2 both have a carboxylate group which superimposes with the carboxylate of all-trans RA, and makes stabilizing hydrogen bonds with Arg 274 and 278, and the backbone nitrogen of Ser 289 (Fig. 5). All other receptor/ligand interactions are hydrophobic. As a result, the size and flexibility of the ligand as well as the shape complementarity with the receptor are critical for affinity and specificity.

Bottom Line: Thirty ligand candidates were tested in vitro.Two novel agonists resulting from the predicted receptor model were active at 50 nM.One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Structural Biology, Skirball Institute of Biomolecular Medicine, New York, USA. schapira@saturn.med.nyu.edu

ABSTRACT

Background: Several Retinoic Acid Receptors (RAR) agonists have therapeutic activity against a variety of cancer types; however, unacceptable toxicity profiles have hindered the development of drugs. RAR agonists presenting novel structural and chemical features could therefore open new avenues for the discovery of leads against breast, lung and prostate cancer or leukemia.

Results: We have analysed the induced fit of the active site residues upon binding of a known ligand. The derived binding site models were used to dock over 150,000 molecules in silico (or virtually) to the structure of the receptor with the Internal Coordinates Mechanics (ICM) program. Thirty ligand candidates were tested in vitro.

Conclusions: Two novel agonists resulting from the predicted receptor model were active at 50 nM. One of them displays novel structural features which may translate into the development of new ligands for cancer therapy.

Show MeSH
Related in: MedlinePlus