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A new structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors.

Dong X, Zheng W - Curr Chem Genomics (2008)

Bottom Line: Our method can also identify critical pharmacophore features that are responsible for the inhibitory potency of the small molecules.Thus, this structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors.The success of this study has also laid a solid foundation for systematic QSAR modeling of the PDE family of enzymes, which will ultimately contribute to chemical genomics research and drug discovery targeting the PDE enzymes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central, University, 1801 Fayetteville Street, Durham, NC 27707, USA.

ABSTRACT
We describe the application of a new QSAR (quantitative structure-activity relationship) formalism to the analysis and modeling of PDE-4 inhibitors. This new method takes advantage of the X-ray structural information of the PDE-4 enzyme to characterize the small molecule inhibitors. It calculates molecular descriptors based on the matching of their pharmacophore feature pairs with those (the reference) of the target binding pocket. Since the reference is derived from the X-ray crystal structures of the target under study, these descriptors are target-specific and easy to interpret. We have analyzed 35 indole derivative-based PDE-4 inhibitors where Partial Least Square (PLS) analysis has been employed to obtain the predictive models. Compared to traditional QSAR methods such as CoMFA and CoMSIA, our models are more robust and predictive measured by statistics for both the training and test sets of molecules. Our method can also identify critical pharmacophore features that are responsible for the inhibitory potency of the small molecules. Thus, this structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors. The success of this study has also laid a solid foundation for systematic QSAR modeling of the PDE family of enzymes, which will ultimately contribute to chemical genomics research and drug discovery targeting the PDE enzymes.

No MeSH data available.


a. 3D rendering of the pharmacophore features derived from Ligand-bound PDE4 structure using the LigandScout program. b. 2D depiction of the pharmacophore features perceived from the Ligand-bound PDE4 structure using the LigandScout program.
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Figure 5: a. 3D rendering of the pharmacophore features derived from Ligand-bound PDE4 structure using the LigandScout program. b. 2D depiction of the pharmacophore features perceived from the Ligand-bound PDE4 structure using the LigandScout program.

Mentions: As described before (Cf. Method), LigandScout was used to analyze the interactions between PDE-4 inhibitors and the binding site of PDE-4, based on the X-ray structure of the inhibitor-bound PDE-4 (1xon.pdb). This analysis has revealed nine pharmacophore centers. The 3D rendering and the 2D depiction of the interactions are shown in Fig. (5a) and Fig. (5b), respectively. The following occupies the four hydrophobic centers: the cyclopentane ring, two chlorine atoms on the pyridine ring, and the central benzene ring. The cyclopentane ring interacts with hydrophobic residues in the PDE-4 binding pocket: MET337, MET357, PHE340, PHE372, and ILE336. Chlorines on the pyridine ring interact with hydrophobic residues MET273, PHE340, ILE336, and LEU319, and the central benzene ring interacts with ILE336, PHE372 and TYR159. The amide nitrogen occupies a hydrogen bond donor center, which interacts with a water molecule that serves as a bridge to the enzyme’s binding pocket. Four hydrogen bond acceptor centers are identified and they are occupied by the following atoms/groups: the methoxy oxygen on the benzene ring, amide oxygen, pyridine nitrogen, and the ether oxygen (connecting the benzene and the cyclopentane rings). The methoxy oxygen and the ether oxygen atoms both interact with GLN369. The amide oxygen and the pyridine nitrogen interact with the small molecule EDO744 and a water molecule, respectively.


A new structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors.

Dong X, Zheng W - Curr Chem Genomics (2008)

a. 3D rendering of the pharmacophore features derived from Ligand-bound PDE4 structure using the LigandScout program. b. 2D depiction of the pharmacophore features perceived from the Ligand-bound PDE4 structure using the LigandScout program.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803435&req=5

Figure 5: a. 3D rendering of the pharmacophore features derived from Ligand-bound PDE4 structure using the LigandScout program. b. 2D depiction of the pharmacophore features perceived from the Ligand-bound PDE4 structure using the LigandScout program.
Mentions: As described before (Cf. Method), LigandScout was used to analyze the interactions between PDE-4 inhibitors and the binding site of PDE-4, based on the X-ray structure of the inhibitor-bound PDE-4 (1xon.pdb). This analysis has revealed nine pharmacophore centers. The 3D rendering and the 2D depiction of the interactions are shown in Fig. (5a) and Fig. (5b), respectively. The following occupies the four hydrophobic centers: the cyclopentane ring, two chlorine atoms on the pyridine ring, and the central benzene ring. The cyclopentane ring interacts with hydrophobic residues in the PDE-4 binding pocket: MET337, MET357, PHE340, PHE372, and ILE336. Chlorines on the pyridine ring interact with hydrophobic residues MET273, PHE340, ILE336, and LEU319, and the central benzene ring interacts with ILE336, PHE372 and TYR159. The amide nitrogen occupies a hydrogen bond donor center, which interacts with a water molecule that serves as a bridge to the enzyme’s binding pocket. Four hydrogen bond acceptor centers are identified and they are occupied by the following atoms/groups: the methoxy oxygen on the benzene ring, amide oxygen, pyridine nitrogen, and the ether oxygen (connecting the benzene and the cyclopentane rings). The methoxy oxygen and the ether oxygen atoms both interact with GLN369. The amide oxygen and the pyridine nitrogen interact with the small molecule EDO744 and a water molecule, respectively.

Bottom Line: Our method can also identify critical pharmacophore features that are responsible for the inhibitory potency of the small molecules.Thus, this structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors.The success of this study has also laid a solid foundation for systematic QSAR modeling of the PDE family of enzymes, which will ultimately contribute to chemical genomics research and drug discovery targeting the PDE enzymes.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central, University, 1801 Fayetteville Street, Durham, NC 27707, USA.

ABSTRACT
We describe the application of a new QSAR (quantitative structure-activity relationship) formalism to the analysis and modeling of PDE-4 inhibitors. This new method takes advantage of the X-ray structural information of the PDE-4 enzyme to characterize the small molecule inhibitors. It calculates molecular descriptors based on the matching of their pharmacophore feature pairs with those (the reference) of the target binding pocket. Since the reference is derived from the X-ray crystal structures of the target under study, these descriptors are target-specific and easy to interpret. We have analyzed 35 indole derivative-based PDE-4 inhibitors where Partial Least Square (PLS) analysis has been employed to obtain the predictive models. Compared to traditional QSAR methods such as CoMFA and CoMSIA, our models are more robust and predictive measured by statistics for both the training and test sets of molecules. Our method can also identify critical pharmacophore features that are responsible for the inhibitory potency of the small molecules. Thus, this structure-based QSAR method affords both descriptive and predictive models for phosphodiesterase-4 inhibitors. The success of this study has also laid a solid foundation for systematic QSAR modeling of the PDE family of enzymes, which will ultimately contribute to chemical genomics research and drug discovery targeting the PDE enzymes.

No MeSH data available.