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Molecular docking studies of Traditional Chinese Medicinal compounds against known protein targets to treat non-small cell lung carcinomas.

Zhao GF, Huang ZA, Du XK, Yang ML, Huang DD, Zhang S - Mol Med Rep (2016)

Bottom Line: In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy.The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC).After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiothoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.

ABSTRACT
In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy. The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC). After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation. Triptolide, a top compound identified by this vigorous in silico screening, was then tested in vitro on the H2347 cell line carrying wild-type EGFR, revealing an anti-proliferative potency similar to that of known drugs against NSCLC.

No MeSH data available.


Related in: MedlinePlus

Two-dimensional representation of the binding modes of (A) matrine, (B) triptolide and (C) hydoxyjolkinolide B.
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f3-mmr-14-02-1132: Two-dimensional representation of the binding modes of (A) matrine, (B) triptolide and (C) hydoxyjolkinolide B.

Mentions: The identified lead compounds were further screened using the Lamarkian algorithm-based AutoDock 4.2 suit. The flexible docking approach of 50 GA runs of maximum evaluations was performed for the top 67 compounds. The 67 compounds were screened from the second dataset of 337 compounds using ADME/Tox analysis, with cutoff based on the parameters set by Lipinski. Out of these 67 compounds, three candidates showed physical interaction with the ATP binding pocket of the kinase domain of EGFR (Fig. 2). In Table I, the top three compounds were ranked on the basis of their binding free energy. The top ranked compound based on docking score was matrine, an alkaloid present in Sophora flarescens. The compound showed a binding energy of −6.19 kcal/mol and was indicated to form single hydrogen bonds with ARG836 of the crystal structure of EGFR as shown in Fig. 3A. The oxygen at the first position of matrine engages in a hydrogen bond with the hydrogen at the 11th position of ARG836 over a distance of 1.91 Å. The second ranked compound was triptolide, a diterpenoid epoxide present in Tripterygium wilfordii, also known as thunder god vine. The compound formed two hydrogen bonds with the ATP binding pocket of EGFR with a binding free energy of −5.69 kcal/mol (Fig. 3B). The hydrogen bonds formed between oxygen in the first position and hydrogen in position 40 of triptolide with HZ2 of LYS757 and OD2 of ASP761 had a bond distance of 2.03 and 1.71 Å, respectively. The compound ranked third regarding interaction with the ATP binding domain of EGFR was hydroxyjolkinolide B, found in Euphorbia fischeriana, with a binding free energy of −3.19 kcal/mol. Two hydroxy groups engaged in hydrogen bonds with ALA859 and one hydrogen bond was present between another hydroxy group and PHE856 over distances of 1.93 and 1.81 Å, respectively. Furthermore, pi-pi interactions of the aromatic core with LYS757 and ARG836 were observed (Fig. 3C). In Table II, the Lipinski rule of five properties of the top three compounds are listed. Three-dimensional representations of the binding interactions at the atomic level are shown in Fig. 4.


Molecular docking studies of Traditional Chinese Medicinal compounds against known protein targets to treat non-small cell lung carcinomas.

Zhao GF, Huang ZA, Du XK, Yang ML, Huang DD, Zhang S - Mol Med Rep (2016)

Two-dimensional representation of the binding modes of (A) matrine, (B) triptolide and (C) hydoxyjolkinolide B.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940108&req=5

f3-mmr-14-02-1132: Two-dimensional representation of the binding modes of (A) matrine, (B) triptolide and (C) hydoxyjolkinolide B.
Mentions: The identified lead compounds were further screened using the Lamarkian algorithm-based AutoDock 4.2 suit. The flexible docking approach of 50 GA runs of maximum evaluations was performed for the top 67 compounds. The 67 compounds were screened from the second dataset of 337 compounds using ADME/Tox analysis, with cutoff based on the parameters set by Lipinski. Out of these 67 compounds, three candidates showed physical interaction with the ATP binding pocket of the kinase domain of EGFR (Fig. 2). In Table I, the top three compounds were ranked on the basis of their binding free energy. The top ranked compound based on docking score was matrine, an alkaloid present in Sophora flarescens. The compound showed a binding energy of −6.19 kcal/mol and was indicated to form single hydrogen bonds with ARG836 of the crystal structure of EGFR as shown in Fig. 3A. The oxygen at the first position of matrine engages in a hydrogen bond with the hydrogen at the 11th position of ARG836 over a distance of 1.91 Å. The second ranked compound was triptolide, a diterpenoid epoxide present in Tripterygium wilfordii, also known as thunder god vine. The compound formed two hydrogen bonds with the ATP binding pocket of EGFR with a binding free energy of −5.69 kcal/mol (Fig. 3B). The hydrogen bonds formed between oxygen in the first position and hydrogen in position 40 of triptolide with HZ2 of LYS757 and OD2 of ASP761 had a bond distance of 2.03 and 1.71 Å, respectively. The compound ranked third regarding interaction with the ATP binding domain of EGFR was hydroxyjolkinolide B, found in Euphorbia fischeriana, with a binding free energy of −3.19 kcal/mol. Two hydroxy groups engaged in hydrogen bonds with ALA859 and one hydrogen bond was present between another hydroxy group and PHE856 over distances of 1.93 and 1.81 Å, respectively. Furthermore, pi-pi interactions of the aromatic core with LYS757 and ARG836 were observed (Fig. 3C). In Table II, the Lipinski rule of five properties of the top three compounds are listed. Three-dimensional representations of the binding interactions at the atomic level are shown in Fig. 4.

Bottom Line: In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy.The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC).After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiothoracic Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.

ABSTRACT
In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy. The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC). After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation. Triptolide, a top compound identified by this vigorous in silico screening, was then tested in vitro on the H2347 cell line carrying wild-type EGFR, revealing an anti-proliferative potency similar to that of known drugs against NSCLC.

No MeSH data available.


Related in: MedlinePlus