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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

Docking of a known RAR-α specific agonist. The RAR-α selective agonist Am580 was docked into the modeled ligand binding pocket of RAR-α . A: The complexed ligand (white sticks) superimposes with the crystal structure of bound all-trans RA (green). Hydrogens are not shown for clarity. B: Am580 (CPK display) fits tightly into the receptor's pocket (yellow wire), but for a ketone oxygen, which shares an hydrogen with Ser234 of the receptor (displayed as stick). The receptor in the vicinity of the ligand is shown as a white ribbon. Carbons, hydrogens, oxygens and nitrogen are colored white, gray, red and blue respectively. (Image generated with Molsoft ICM)
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Figure 2: Docking of a known RAR-α specific agonist. The RAR-α selective agonist Am580 was docked into the modeled ligand binding pocket of RAR-α . A: The complexed ligand (white sticks) superimposes with the crystal structure of bound all-trans RA (green). Hydrogens are not shown for clarity. B: Am580 (CPK display) fits tightly into the receptor's pocket (yellow wire), but for a ketone oxygen, which shares an hydrogen with Ser234 of the receptor (displayed as stick). The receptor in the vicinity of the ligand is shown as a white ribbon. Carbons, hydrogens, oxygens and nitrogen are colored white, gray, red and blue respectively. (Image generated with Molsoft ICM)

Mentions: In order to address the accuracy of our model of the RAR-α binding pocket, we docked Am580, an RAR-α specific agonist [19], into the receptor (the chemical structure of Am580 is shown Fig. 1b). A rapid docking procedure with flexible ligand and a grid representation of the receptor was followed by an extensive Monte Carlo energy minimization with both ligand and receptor side chains flexible (see "Materials and Methods" for details). The ligand superimposed well with the natural hormone all-trans RA (Fig. 2a). Interestingly, Am580 does not seem to fit in the receptor binding site: the ketone oxygen of the ligand sticks out of the binding pocket, due to too close proximity of residue 234 (Fig. 2b). However, in the complex with RAR-α, this ketone oxygen shares an hydrogen atom with the hydroxyl group of serine 234, and forms a stabilizing hydrogen bond, while a steric clash occurs in the other two RAR isoforms, where residue 234 is an alanine. Consequently, our model provides a rational for Am580 isoform specificity, suggesting that it is relevant and could be used as a template for the discovery of novel RAR-α agonist structures.


In silico discovery of novel retinoic acid receptor agonist structures.

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

Docking of a known RAR-α specific agonist. The RAR-α selective agonist Am580 was docked into the modeled ligand binding pocket of RAR-α . A: The complexed ligand (white sticks) superimposes with the crystal structure of bound all-trans RA (green). Hydrogens are not shown for clarity. B: Am580 (CPK display) fits tightly into the receptor's pocket (yellow wire), but for a ketone oxygen, which shares an hydrogen with Ser234 of the receptor (displayed as stick). The receptor in the vicinity of the ligand is shown as a white ribbon. Carbons, hydrogens, oxygens and nitrogen are colored white, gray, red and blue respectively. (Image generated with Molsoft ICM)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC32304&req=5

Figure 2: Docking of a known RAR-α specific agonist. The RAR-α selective agonist Am580 was docked into the modeled ligand binding pocket of RAR-α . A: The complexed ligand (white sticks) superimposes with the crystal structure of bound all-trans RA (green). Hydrogens are not shown for clarity. B: Am580 (CPK display) fits tightly into the receptor's pocket (yellow wire), but for a ketone oxygen, which shares an hydrogen with Ser234 of the receptor (displayed as stick). The receptor in the vicinity of the ligand is shown as a white ribbon. Carbons, hydrogens, oxygens and nitrogen are colored white, gray, red and blue respectively. (Image generated with Molsoft ICM)
Mentions: In order to address the accuracy of our model of the RAR-α binding pocket, we docked Am580, an RAR-α specific agonist [19], into the receptor (the chemical structure of Am580 is shown Fig. 1b). A rapid docking procedure with flexible ligand and a grid representation of the receptor was followed by an extensive Monte Carlo energy minimization with both ligand and receptor side chains flexible (see "Materials and Methods" for details). The ligand superimposed well with the natural hormone all-trans RA (Fig. 2a). Interestingly, Am580 does not seem to fit in the receptor binding site: the ketone oxygen of the ligand sticks out of the binding pocket, due to too close proximity of residue 234 (Fig. 2b). However, in the complex with RAR-α, this ketone oxygen shares an hydrogen atom with the hydroxyl group of serine 234, and forms a stabilizing hydrogen bond, while a steric clash occurs in the other two RAR isoforms, where residue 234 is an alanine. Consequently, our model provides a rational for Am580 isoform specificity, suggesting that it is relevant and could be used as a template for the discovery of novel RAR-α agonist structures.

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