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Novel natural inhibitors of CYP1A2 identified by in silico and in vitro screening.

Zhu R, Hu L, Li H, Su J, Cao Z, Zhang W - Int J Mol Sci (2011)

Bottom Line: Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity.The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors.It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.

View Article: PubMed Central - PubMed

Affiliation: Department of Natural Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; E-Mails: rxzhu@tongji.edu.cn (R.Z.); liwei8192@yahoo.com.cn (L.H.); kotorinun@126.com (H.L.); juansu_2008@126.com (J.S.).

ABSTRACT
Inhibition of cytochrome P450 (CYP) is a major cause of herb-drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb-drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.

Show MeSH
The molecular structure of selected template by superposing three bifonazole in three different conformations.
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f2-ijms-12-03250: The molecular structure of selected template by superposing three bifonazole in three different conformations.

Mentions: For the pharmacophore screening, the key step was to choose a good template molecule. In this study, several template molecules (Figure 1) could be obtained to generate the pharmacophore: (1) the substrates extracted from complex structures of CYP1A2 and its homologous enzymes; and (2) inhibitors reported in the literature [24]. Different template molecules based on individual or integrated information above were used to generate the pharmacophores. Then up to 202 different herb integrants tested in vitro by our group were used as the test dataset (supplement Table 2). The molecular structure of selected template was shown in Figure 2. Finally, the pharmacophore model was obtained (Figure 3). The true positive rate and true negative rate of the best pharmacophore model were 84.6% (11/13) and 86.8% (164/189), respectively. Other results of different pharmacophore models are also shown in Table 1 as a comparison.


Novel natural inhibitors of CYP1A2 identified by in silico and in vitro screening.

Zhu R, Hu L, Li H, Su J, Cao Z, Zhang W - Int J Mol Sci (2011)

The molecular structure of selected template by superposing three bifonazole in three different conformations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3116189&req=5

f2-ijms-12-03250: The molecular structure of selected template by superposing three bifonazole in three different conformations.
Mentions: For the pharmacophore screening, the key step was to choose a good template molecule. In this study, several template molecules (Figure 1) could be obtained to generate the pharmacophore: (1) the substrates extracted from complex structures of CYP1A2 and its homologous enzymes; and (2) inhibitors reported in the literature [24]. Different template molecules based on individual or integrated information above were used to generate the pharmacophores. Then up to 202 different herb integrants tested in vitro by our group were used as the test dataset (supplement Table 2). The molecular structure of selected template was shown in Figure 2. Finally, the pharmacophore model was obtained (Figure 3). The true positive rate and true negative rate of the best pharmacophore model were 84.6% (11/13) and 86.8% (164/189), respectively. Other results of different pharmacophore models are also shown in Table 1 as a comparison.

Bottom Line: Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity.The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors.It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.

View Article: PubMed Central - PubMed

Affiliation: Department of Natural Medicinal Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China; E-Mails: rxzhu@tongji.edu.cn (R.Z.); liwei8192@yahoo.com.cn (L.H.); kotorinun@126.com (H.L.); juansu_2008@126.com (J.S.).

ABSTRACT
Inhibition of cytochrome P450 (CYP) is a major cause of herb-drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb-drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.

Show MeSH