QSAR, docking and ADMET studies of camptothecin derivatives as inhibitors of DNA topoisomerase‐I

Yadav, Dharmendra Kumar; Khan, Feroz

doi:10.1002/cem.2488

Cited by 51 publications

(25 citation statements)

References 34 publications

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“…The external validation or predictive capacity of the derived model was judged by predictive

r^{2} (r_{pred}^{2})

as shown in the following equation:

r_{pred}^{2} = 1 - \frac{\sum {({normalY}_{pred (test)} - {normalY}_{(test)})}^{2}}{\sum {({normalY}_{(test)} - {normalY}_{(training)})}^{2}}

where Y pred (test) and Y (test) indicate the predicted and observed activity values, respectively, for test set compounds and

{\bar{normalY}}_{(training)}

indicates the average bioactivity of compound in the training set. An acceptable predictive power of a QSAR model

(r_{pred}^{2})

should be >0.6 for the test set molecules 33–35…”

Section: Methodsmentioning

confidence: 99%

Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer

Yadav

Kumar

Saloni

et al. 2017

DDDT

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Withanolides are a group of pharmacologically active compounds present in most prodigal amounts in roots and leaves of Withania somnifera (Indian ginseng), one of the most important medicinal plants of Indian traditional practice of medicine. Withanolides are steroidal lactones (highly oxygenated C-28 phytochemicals) and have been reported to exhibit immunomodulatory, anticancer and other activities. In the present study, a quantitative structure activity relationship (QSAR) model was developed by a forward stepwise multiple linear regression method to predict the activity of withanolide analogs against human breast cancer. The most effective QSAR model for anticancer activity against the SK-Br-3 cell showed the best correlation with activity (r2=0.93 and rCV2 =0.90). Similarly, cross-validation regression coefficient (rCV2=0.85) of the best QSAR model against the MCF7/BUS cells showed a high correlation (r2=0.91). In particular, compounds CID_73621, CID_435144, CID_301751 and CID_3372729 have a marked antiproliferative activity against the MCF7/BUS cells, while 2,3-dihydrowithaferin A-3-beta-O-sulfate, withanolide 5, withanolide A, withaferin A, CID_10413139, CID_11294368, CID_53477765, CID_135887, CID_301751 and CID_3372729 have a high activity against the Sk-Br-3 cells compared to standard drugs 5-fluorouracil (5-FU) and camptothecin. Molecular docking was performed to study the binding conformations and different bonding behaviors, in order to reveal the plausible mechanism of action behind higher accumulation of active withanolide analogs with β-tubulin. The results of the present study may help in the designing of lead compound with improved activity.

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“…The external validation or predictive capacity of the derived model was judged by predictive

r^{2} (r_{pred}^{2})

as shown in the following equation:

r_{pred}^{2} = 1 - \frac{\sum {({normalY}_{pred (test)} - {normalY}_{(test)})}^{2}}{\sum {({normalY}_{(test)} - {normalY}_{(training)})}^{2}}

where Y pred (test) and Y (test) indicate the predicted and observed activity values, respectively, for test set compounds and

{\bar{normalY}}_{(training)}

indicates the average bioactivity of compound in the training set. An acceptable predictive power of a QSAR model

(r_{pred}^{2})

should be >0.6 for the test set molecules 33–35…”

Section: Methodsmentioning

confidence: 99%

Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer

Yadav

Kumar

Saloni

et al. 2017

DDDT

Self Cite

View full text Add to dashboard Cite

show abstract

“…To find the possible bioactive conformations of control, compound 1 and its derivative 1e , the Sybyl‐X v1.3 interfaced with Surflex‐Dock program was used to dock the ligands into the active site of E. coli YojI protein. During docking procedure all parameters were assigned to there default values .…”

Section: Methodsmentioning

confidence: 99%

4‐Hydroxy‐α‐Tetralone and its Derivative as Drug Resistance Reversal Agents in Multi Drug Resistant Escherichia coli

et al. 2014

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The purpose of present investigation was to understand the drug resistance reversal mechanism of 4-hydroxy-α-tetralone (1) isolated from Ammannia spp. along with its semi-synthetic derivatives (1a-1e) using multidrug resistant Escherichia coli (MDREC). The test compounds did not show significant antibacterial activity of their own, but in combination, they reduced the minimum inhibitory concentration (MIC) of tetracycline (TET). In time kill assay, compound 1 and its derivative 1e in combination with TET reduced the cell viability in concentration dependent manner. Compounds 1 and 1e were also able to reduce the mutation prevention concentration of TET. Both compounds showed inhibition of ATP dependent efflux pumps. In real time polymerase chain reaction (RT-PCR) study, compounds 1 and 1e alone and in combination with TET showed significant down expression of efflux pump gene (yojI) encoding multidrug ATP binding cassettes (ABC) transporter protein. Molecular mechanism was also supported by the in silico docking studies, which revealed significant binding affinity of compounds 1 and 1e with YojI. This study confirms that compound 1 and its derivative 1e are ABC efflux pump inhibitors which may be the basis for development of antibacterial combinations for the management of MDR infections from inexpensive natural product.

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“…The calculated TPSA values of these compounds were within acceptable limits. The distribution of compounds in the human body was described by the predicted blood–brain barrier coefficient (logBB), apparent Caco-2 permeability, log Kp for skin permeability, volume of distribution and plasma protein binding (log Khsa for serum protein binding)424344. All compounds show poor aqueous solubility (Table 1 in Supplementary Information).…”

Section: Resultsmentioning

confidence: 99%

New arylated benzo[h]quinolines induce anti-cancer activity by oxidative stress-mediated DNA damage

Yadav

Rai

Kumar

et al. 2016

Sci Rep

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The anti-cancer activity of the benzo[h]quinolines was evaluated on cultured human skin cancer (G361), lung cancer (H460), breast cancer (MCF7) and colon cancer (HCT116) cell lines. The inhibitory effect of these compounds on the cell growth was determined by the MTT assay. The compounds 3e, 3f, 3h and 3j showed potential cytotoxicity against these human cancer cell lines. Effect of active compounds on DNA oxidation and expression of apoptosis related gene was studied. We also developed a quantitative method to measure the activity of cyclin-dependent kinases-2 (CDK2) by western blotting in the presence of active compound. In addition, molecular docking revealed that benzo[h]quinolines can correctly dock into the hydrophobic pocket of the targets receptor protein aromatase and CDK2, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. These findings reveal that benzo[h]quinolines act as anti-cancer agents by inducing oxidative stress-mediated DNA damage.

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QSAR, docking and ADMET studies of camptothecin derivatives as inhibitors of DNA topoisomerase‐I

Cited by 51 publications

References 34 publications

Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer

Molecular docking, QSAR and ADMET studies of withanolide analogs against breast cancer

4‐Hydroxy‐α‐Tetralone and its Derivative as Drug Resistance Reversal Agents in Multi Drug Resistant Escherichia coli

New arylated benzo[h]quinolines induce anti-cancer activity by oxidative stress-mediated DNA damage

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