[논문]Hologram Based QSAR Analysis of Caspase-3 Inhibitors

Sathya., B

doi:10.13160/ricns.2018.11.2.93

Hologram Based QSAR Analysis of Caspase-3 Inhibitors 원문보기

Journal of the Chosun Natural Science = 조선자연과학논문집, v.11 no.2, 2018년, pp.93 - 100

Sathya., B (Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology)

Abstract ▼ AI-Helper

Caspases, a family of cysteinyl aspartate-specific proteases plays a central role in the regulation and the execution of apoptotic cell death. Caspase-3 has been proven to be an effective target for reducing the amount of cellular and tissue damage because the activation of caspases-3 stimulates a signalling pathway that ultimately leads to the death of the cell. In this study, Hologram based Quantitative Structure Activity Relationship (HQSAR) models was generated on a series of Caspase-3 inhibitors named 3, 4-dihydropyrimidoindolones derivatives. The best HQSAR model was obtained using atoms, bonds, and hydrogen atoms (A/B/H) as fragment distinction parameter using hologram length 61 and 3 components with fragment size of minimum 5 and maximum 8. Significant cross-validated correlation coefficient ($q^2=0.684$) and non cross-validated correlation coefficients ($r^2=0.754$) were obtained. The model was then used to evaluate the eight external test compounds and its $r^2_{pred}$ was found to be 0.559. Contribution map show that presence of pyrrolidine sulfonamide ring and its bulkier substituent's makes big contributions for improving the biological activities of the compounds.

주제어

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문제 정의

This study was conducted to rationalize the dihydropyrimidoindolones derivatives derivatives by HQSAR analysis. All the generated models showed different statistical results in terms of q² and r² values when different combinations of fragment distinction were used.

제안 방법

In the present study, Hologram based Quantitative Structure Activity Relationship models were generated on a series of 3,4-dihydropyrimidoindolones derivatives as Caspase-3 inhibitors. Many HQSAR models were generated with different combinations of parameters and based on statistical values of the model, the best model was selected and its contribution map was also analyzed. We also identified the important features of the compounds for improving the activity which could be used by medicinal chemist to derive future non-peptidic inhibitors of caspase-3 derivatives.
With HQSAR technique we can easily and rapidly generate QSAR models for both small and large data set with high predictive value compared to other QSAR models^[24]. The limitation is that it could not make biological activity predictions accurately to molecules lacking fragments or structural units included in the training set which are used to set up the model. In the present study, Hologram based Quantitative Structure Activity Relationship models were generated on a series of 3,4-dihydropyrimidoindolones derivatives as Caspase-3 inhibitors.

성능/효과

The statistical results of the generated HQSAR models are shown in Table 2. The model selected was further investigated to see the influence of length of fragment sizes (2-5, 3-6, 4-7, 5-8, 6-9, 7-10 and 8-11) and its results are summarized in the Table 3. The statistical parameters showed that there is no much significant improvement by changing the fragment size for this dataset. We had chosen the best model with higher q² values as summarized in Table 3 for examining the predictive ability r²_pred of test set molecules.
559) which was built using parameters A/B/H as fragment distinction, fragment size set to min 5 and max 8 with hologram length 61 and 3 components. The detailed predictions of actual versus predicted activities along with the residual values for training and test set was depicted in Table 4. Low residual values obtained for developed HQSAR model indicates its reliability and can be used to predict the biological activity of novel compounds.

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DOI : 10.13160/ricns.2018.11.2.93
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용어 설명: PCR은 세균 특이성이 있는 primer를 이용하여 적은 수의 세균이 있을지라도 쉽게 검출할 수 있는 유용한 방법이며, 이를 이용하여 구강 내 치면세균막이나 타액에서 직접 세균을 검출할 수 있게 되었다[8].

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