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Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis.

Tambunan US, Wulandari EK - BMC Bioinformatics (2010)

Bottom Line: Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties.Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target.SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Bioinformatics, Department of Chemistry, Faculty of Mathematics and Natural Science, University of Indonesia, Depok 16424, Indonesia. usman@ui.ac.id

ABSTRACT
Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate.

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Related in: MedlinePlus

Structures of docked SAHA with Homo sapiens Class II HDACs. Three Conformations of Structures of docked SAHA with (A) HDAC4, (B) HDAC5, (C) HDAC6, (D) HDAC7, (E) HDAC9 and (F) HDAC10. A surface representation of catalytic domain of Homo sapiens Class II HDACs bound to SAHA. The zinc ion is shown as gray sphere. SAHA are shown as stick models colored as per docked type: red, blue, and yellow. Amino acids coordinating the zinc and forming the trihedrally coordinates are shown as sticks. Some catalytic domain of Homo sapiens Class II HDACs residues interacting with the docked SAHA are shown as stick models. In HDAC4-SAHA, HDAC5-SAHA, HDAC6-SAHA and HDAC7-SAHA complexes, SAHA binds the catalytic zinc ion in a bidentate fashion, with its carbonyl and hydroxyl bound to catalytic zinc ion. Whereas, in HDAC9-SAHA and HDAC10-SAHA complexes bind the catalytic zinc ion in a monodentate fashion, with its carbonyl bound to catalytic zinc ion.
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Figure 3: Structures of docked SAHA with Homo sapiens Class II HDACs. Three Conformations of Structures of docked SAHA with (A) HDAC4, (B) HDAC5, (C) HDAC6, (D) HDAC7, (E) HDAC9 and (F) HDAC10. A surface representation of catalytic domain of Homo sapiens Class II HDACs bound to SAHA. The zinc ion is shown as gray sphere. SAHA are shown as stick models colored as per docked type: red, blue, and yellow. Amino acids coordinating the zinc and forming the trihedrally coordinates are shown as sticks. Some catalytic domain of Homo sapiens Class II HDACs residues interacting with the docked SAHA are shown as stick models. In HDAC4-SAHA, HDAC5-SAHA, HDAC6-SAHA and HDAC7-SAHA complexes, SAHA binds the catalytic zinc ion in a bidentate fashion, with its carbonyl and hydroxyl bound to catalytic zinc ion. Whereas, in HDAC9-SAHA and HDAC10-SAHA complexes bind the catalytic zinc ion in a monodentate fashion, with its carbonyl bound to catalytic zinc ion.

Mentions: To investigate the interaction between Homo sapiens class II HDAC with inhibitors, we docked SAHA and TSA to the six homology models. The results for SAHA and TSA are shown in Figures 3 and 4 while the calculated binding energies are summarized in Table 1. As expected, SAHA and TSA bind in the active site of HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 with a similar pattern. All docked SAHA and TSA structures have the same orientation as in the X-ray structure of the HDAC4-hydroxamic acid cocrystal. In HDAC4-SAHA and HDAC4-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp193, His195, Asp287 (Figures 3 and 4). In HDAC5-SAHA and HDAC5-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp178, His180, Asp272. In HDAC6-SAHA and HDAC6-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp71, His73, Asp164. In HDAC7-SAHA and HDAC7-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp191, His193, Asp285. In HDAC9-SAHA and HDAC9-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp188, His190, Asp282. In HDAC10-SAHA and HDAC10-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp133, His135, Asp226. Amino acid residues that are involved in binding the catalytic zinc are highly conserved in class II HDACs. In HDAC4-SAHA, HDAC5-SAHA, HDAC6-SAHA and HDAC7-SAHA complexes, SAHA binds the catalytic zinc ion in a bidentate fashion, with its carbonyl and hydroxyl bound to catalytic zinc ion. Whereas, in HDAC9-SAHA and HDAC10-SAHA complexes, SAHA binds the catalytic zinc ion in a monodentate fashion with its carbonyl bound to catalytic zinc ion. Except HDAC5-TSA complex, all of Homo sapiens class II HDACs-TSA complexes bind the catalytic zinc ion in a monodentate fashion. The aberrant monodentate coordination of SAHA and TSA in the catalytic domain of Homo sapiens class II HDACs -complexes structures originates from the different topology of the active site [21]. In Homo sapiens class II HDACs-SAHA complexes, the hydroxyl group of SAHA forms hydrogen bonds with the side chains of two active site histidines, mimicking the interactions of the water molecule in the active site of catalytic domain HDAC7 cocrystal. The hydroxyl group of SAHA replaces the water molecule, which was found in the active site of catalytic domain HDAC7 cocrystal. In Homo sapiens class II HDACs-TSA complexes, the hydroxyl group of TSA forms hydrogen bonds with the side chains of two active site histidine and glycine, mimicking the interactions of the water molecule in the active site of catalytic domain HDAC7 cocrystal. The hydroxyl group of SAHA replaces the water molecule, which was found in the active site of catalytic domain HDAC7 cocrystal [22].


Identification of a better Homo sapiens Class II HDAC inhibitor through binding energy calculations and descriptor analysis.

Tambunan US, Wulandari EK - BMC Bioinformatics (2010)

Structures of docked SAHA with Homo sapiens Class II HDACs. Three Conformations of Structures of docked SAHA with (A) HDAC4, (B) HDAC5, (C) HDAC6, (D) HDAC7, (E) HDAC9 and (F) HDAC10. A surface representation of catalytic domain of Homo sapiens Class II HDACs bound to SAHA. The zinc ion is shown as gray sphere. SAHA are shown as stick models colored as per docked type: red, blue, and yellow. Amino acids coordinating the zinc and forming the trihedrally coordinates are shown as sticks. Some catalytic domain of Homo sapiens Class II HDACs residues interacting with the docked SAHA are shown as stick models. In HDAC4-SAHA, HDAC5-SAHA, HDAC6-SAHA and HDAC7-SAHA complexes, SAHA binds the catalytic zinc ion in a bidentate fashion, with its carbonyl and hydroxyl bound to catalytic zinc ion. Whereas, in HDAC9-SAHA and HDAC10-SAHA complexes bind the catalytic zinc ion in a monodentate fashion, with its carbonyl bound to catalytic zinc ion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957684&req=5

Figure 3: Structures of docked SAHA with Homo sapiens Class II HDACs. Three Conformations of Structures of docked SAHA with (A) HDAC4, (B) HDAC5, (C) HDAC6, (D) HDAC7, (E) HDAC9 and (F) HDAC10. A surface representation of catalytic domain of Homo sapiens Class II HDACs bound to SAHA. The zinc ion is shown as gray sphere. SAHA are shown as stick models colored as per docked type: red, blue, and yellow. Amino acids coordinating the zinc and forming the trihedrally coordinates are shown as sticks. Some catalytic domain of Homo sapiens Class II HDACs residues interacting with the docked SAHA are shown as stick models. In HDAC4-SAHA, HDAC5-SAHA, HDAC6-SAHA and HDAC7-SAHA complexes, SAHA binds the catalytic zinc ion in a bidentate fashion, with its carbonyl and hydroxyl bound to catalytic zinc ion. Whereas, in HDAC9-SAHA and HDAC10-SAHA complexes bind the catalytic zinc ion in a monodentate fashion, with its carbonyl bound to catalytic zinc ion.
Mentions: To investigate the interaction between Homo sapiens class II HDAC with inhibitors, we docked SAHA and TSA to the six homology models. The results for SAHA and TSA are shown in Figures 3 and 4 while the calculated binding energies are summarized in Table 1. As expected, SAHA and TSA bind in the active site of HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 with a similar pattern. All docked SAHA and TSA structures have the same orientation as in the X-ray structure of the HDAC4-hydroxamic acid cocrystal. In HDAC4-SAHA and HDAC4-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp193, His195, Asp287 (Figures 3 and 4). In HDAC5-SAHA and HDAC5-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp178, His180, Asp272. In HDAC6-SAHA and HDAC6-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp71, His73, Asp164. In HDAC7-SAHA and HDAC7-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp191, His193, Asp285. In HDAC9-SAHA and HDAC9-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp188, His190, Asp282. In HDAC10-SAHA and HDAC10-TSA complexes, the catalytic zinc trihedrally coordinates to the side chains of amino acids Asp133, His135, Asp226. Amino acid residues that are involved in binding the catalytic zinc are highly conserved in class II HDACs. In HDAC4-SAHA, HDAC5-SAHA, HDAC6-SAHA and HDAC7-SAHA complexes, SAHA binds the catalytic zinc ion in a bidentate fashion, with its carbonyl and hydroxyl bound to catalytic zinc ion. Whereas, in HDAC9-SAHA and HDAC10-SAHA complexes, SAHA binds the catalytic zinc ion in a monodentate fashion with its carbonyl bound to catalytic zinc ion. Except HDAC5-TSA complex, all of Homo sapiens class II HDACs-TSA complexes bind the catalytic zinc ion in a monodentate fashion. The aberrant monodentate coordination of SAHA and TSA in the catalytic domain of Homo sapiens class II HDACs -complexes structures originates from the different topology of the active site [21]. In Homo sapiens class II HDACs-SAHA complexes, the hydroxyl group of SAHA forms hydrogen bonds with the side chains of two active site histidines, mimicking the interactions of the water molecule in the active site of catalytic domain HDAC7 cocrystal. The hydroxyl group of SAHA replaces the water molecule, which was found in the active site of catalytic domain HDAC7 cocrystal. In Homo sapiens class II HDACs-TSA complexes, the hydroxyl group of TSA forms hydrogen bonds with the side chains of two active site histidine and glycine, mimicking the interactions of the water molecule in the active site of catalytic domain HDAC7 cocrystal. The hydroxyl group of SAHA replaces the water molecule, which was found in the active site of catalytic domain HDAC7 cocrystal [22].

Bottom Line: Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties.Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target.SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Bioinformatics, Department of Chemistry, Faculty of Mathematics and Natural Science, University of Indonesia, Depok 16424, Indonesia. usman@ui.ac.id

ABSTRACT
Human papillomaviruses (HPVs) are the most common on sexually transmitted viruses in the world. HPVs are responsible for a large spectrum of deseases, both benign and malignant. The certain types of HPV are involved in the development of cervical cancer. In attemps to find additional drugs in the treatment of cervical cancer, inhibitors of the histone deacetylases (HDAC) have received much attention due to their low cytotoxic profiles and the E6/E7 oncogene function of human papilomavirus can be completely by passed by HDAC inhibition. The histone deacetylase inhibitors can induce growth arrest, differentiation and apoptosis of cancer cells. HDAC class I and class II are considered the main targets for cancer. Therefore, the six HDACs class II was modeled and about two inhibitors (SAHA and TSA) were docked using AutoDock4.2, to each of the inhibitor in order to identify the pharmacological properties. Based on the results of docking, SAHA and TSA were able to bind with zinc ion in HDACs models as a drug target. SAHA was satisfied almost all the properties i.e., binding affinity, the Drug-Likeness value and Drug Score with 70% oral bioavailability and the carbonyl group of these compound fits well into the active site of the target where the zinc is present. Hence, SAHA could be developed as potential inhibitors of class II HDACs and valuable cervical cancer drug candidate.

Show MeSH
Related in: MedlinePlus