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Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.

Li BQ, Niu B, Chen L, Wei ZJ, Huang T, Jiang M, Lu J, Zheng MY, Kong XY, Cai YD - PLoS ONE (2013)

Bottom Line: In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention.In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy.In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

ABSTRACT
Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.

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Related in: MedlinePlus

Non-nucleoside analog’s butterfly-like shape drawn with software chemoffice and Pymol.The structure was retrieved from PubChem with the ID 60847. Dot surface is colored according to atom types.
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pone-0065207-g006: Non-nucleoside analog’s butterfly-like shape drawn with software chemoffice and Pymol.The structure was retrieved from PubChem with the ID 60847. Dot surface is colored according to atom types.

Mentions: Other chemicals targeting HIV-1 RT including CID100060847 (BHAP), CID100004463 (nevirapine), CID105495818 (BMS-378806) could be classified to NNRTIs. Different to NARTIs, NNRTIs have two symmetrical aromatic rings, which show special butterfly-like shape (Fig. 6) [65], [66]. Five β-sheets of P66 form a pocket which is composed of hydrophobic amino acids. Based on hydrophobic, hydrogen bonding and π-π stacking interaction derived from aromatic ring of aromatic amino acids, the aromatic rings from one side of these three chemicals can interact with aromatic amino acids including Tyr181, Tyr188, Phe227, Trp229 and those from another side can interact with hydrophobic amino acids including Val179, Val106 and Leul00. Therefore, a small hydrophobic pocket is formed by Tyr181, Tyr183 and Tyr188. As the three amino acids rotate outside, the entrance of the pocket will be exposed where HIV-1 RT can bind to these three chemicals. In this case, the relative locations of β4, β7 and β8 sheets will change. Complementary rearrangement of the conformation of RT and CID100060847 (BHAP), CID100004463 (nevirapine), CID105495818 (BMS-378806) result in hydrophobic interactions [64], [67], [68]. As a result, the conformation of the newly located catalytic active site is similar to that of P51 [16]. Therefore, the new conformation is inactive. This is the reason why non-nucleoside analog has the ability to inhibit the RT by changing the conformation of catalytic site.


Identifying chemicals with potential therapy of HIV based on protein-protein and protein-chemical interaction network.

Li BQ, Niu B, Chen L, Wei ZJ, Huang T, Jiang M, Lu J, Zheng MY, Kong XY, Cai YD - PLoS ONE (2013)

Non-nucleoside analog’s butterfly-like shape drawn with software chemoffice and Pymol.The structure was retrieved from PubChem with the ID 60847. Dot surface is colored according to atom types.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675210&req=5

pone-0065207-g006: Non-nucleoside analog’s butterfly-like shape drawn with software chemoffice and Pymol.The structure was retrieved from PubChem with the ID 60847. Dot surface is colored according to atom types.
Mentions: Other chemicals targeting HIV-1 RT including CID100060847 (BHAP), CID100004463 (nevirapine), CID105495818 (BMS-378806) could be classified to NNRTIs. Different to NARTIs, NNRTIs have two symmetrical aromatic rings, which show special butterfly-like shape (Fig. 6) [65], [66]. Five β-sheets of P66 form a pocket which is composed of hydrophobic amino acids. Based on hydrophobic, hydrogen bonding and π-π stacking interaction derived from aromatic ring of aromatic amino acids, the aromatic rings from one side of these three chemicals can interact with aromatic amino acids including Tyr181, Tyr188, Phe227, Trp229 and those from another side can interact with hydrophobic amino acids including Val179, Val106 and Leul00. Therefore, a small hydrophobic pocket is formed by Tyr181, Tyr183 and Tyr188. As the three amino acids rotate outside, the entrance of the pocket will be exposed where HIV-1 RT can bind to these three chemicals. In this case, the relative locations of β4, β7 and β8 sheets will change. Complementary rearrangement of the conformation of RT and CID100060847 (BHAP), CID100004463 (nevirapine), CID105495818 (BMS-378806) result in hydrophobic interactions [64], [67], [68]. As a result, the conformation of the newly located catalytic active site is similar to that of P51 [16]. Therefore, the new conformation is inactive. This is the reason why non-nucleoside analog has the ability to inhibit the RT by changing the conformation of catalytic site.

Bottom Line: In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention.In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy.In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.

ABSTRACT
Acquired immune deficiency syndrome (AIDS) is a severe infectious disease that causes a large number of deaths every year. Traditional anti-AIDS drugs directly targeting the HIV-1 encoded enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) usually suffer from drug resistance after a period of treatment and serious side effects. In recent years, the emergence of numerous useful information of protein-protein interactions (PPI) in the HIV life cycle and related inhibitors makes PPI a new way for antiviral drug intervention. In this study, we identified 26 core human proteins involved in PPI between HIV-1 and host, that have great potential for HIV therapy. In addition, 280 chemicals that interact with three HIV drugs targeting human proteins can also interact with these 26 core proteins. All these indicate that our method as presented in this paper is quite promising. The method may become a useful tool, or at least plays a complementary role to the existing method, for identifying novel anti-HIV drugs.

Show MeSH
Related in: MedlinePlus