From the Manual Method of Topliss to a Modified Quantitative Method

Ra, Yunes; Ve, Heinzen; Filho, Cechinel; Lazzarotto, Marcelo

doi:10.1055/s-0031-1299868

Cited by 2 publications

(6 citation statements)

References 11 publications

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“…As was observed in our previous study [2], there are some particular series (examples 20, 21, 28 and 29 of reference [2]) in which the best reduced correlation does not correspond to the best total correlation. In order to deal with these cases it was necessary to include two substituents that according to the best reduced correlations predict the compounds that will exhibit the greatest potency of activity.…”

Section: Application Of the Methods Where The Best Reduced Correlationsupporting

confidence: 72%

“…Fujita et al obtained similar results using a multiple regression with the following equation: 0.917 [29] inhibitors of DHFR from L. tropica MR+σ [30] murine leukemia DHFR L5178Y (anti tumor) MR-π 2…”

Section: Application Of the Methods Where The Best Reduced Correlationmentioning

confidence: 71%

“…2. The value for the correlation coefficient, r, as was indicated in our previous study [2], should be r Ն 0.71, indicating a coefficient of determination r 2 > 0.50, meaning that the straight line regression explains more than 50 % of the total "y" (experimental points) variation.…”

Section: Methodsmentioning

confidence: 74%

“…Linear regression analysis was applied to the value for experimental biological activity of each series of compounds, obtained from the literature [10−58], and the parameters of the molecular structure π and σ suggested by Topliss [4], including the parameters Es and MR, in order to evaluate quantitatively the steric effects, and some combinations of them, similar to those used in a previous study [2] but with the addition of MR-π 2 . This parameter is considered similar to the Topliss 2π-π 2 because MR is a physicochemical property that gives information about the London dispersion forces that are related to the lipophilicity [5−8].…”

Section: Methodsmentioning

confidence: 99%

“…Recently [2] we proposed a Modified Topliss Method (MTM) that consists of quantitative correlation by single regression analysis of the activity of a series of 4 or 5 substituted aromatic compounds, with their hydrophilic (π), electronic (σ) and steric (Es and MR) descriptors and some combinations of them in order to predict a new synthesis or to obtain a training set of compounds for application of the most advanced experimental design methods.…”

Section: Introductionmentioning

confidence: 99%

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Optimized Modified Topliss Method: A Tool for Quantitative Structure-Activity Relationship Studies

Lazzarotto

Heinzen

Yunes

2011

Arzneimittelforschung

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The structural variation of lead compounds often includes the variation of substituents at a particular site. A common difficulty, in quantitative structure-activity relationship (QSAR) studies, is to select the best substituents to obtain, with a minimum number of experiments, a major change in some impor. tant properties of the molecule. To improve a proposed modified Topliss method, 187 different substituted compounds belonging to 70 series were studied. A single linear regression was carried out between the experimental activity of each series of compounds and the molecular structure parameters pi, sigma, Es and MR, along with some combinations of them, in order to select the best substituents for constructing the "reduced" correlation. This selection considered the scaled smallest residue average of the substituent, the number of times that the substituent is inserted in the 70 series and its quadrant in the Craig graph. The results obtained in this study with this simple method showed a good predictive capacity when compared with the multiple regression analysis, using the Hansch method.

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Section: Application Of the Methods Where The Best Reduced Correlationsupporting

confidence: 72%

Section: Application Of the Methods Where The Best Reduced Correlationmentioning

confidence: 71%

Section: Methodsmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Optimized Modified Topliss Method: A Tool for Quantitative Structure-Activity Relationship Studies

Lazzarotto

Heinzen

Yunes

2011

Arzneimittelforschung

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Hubungan Kuantitatif Struktur-Aktivitas dan Desain Senyawa Novel Phenyl Benzimidazoles sebagai Penghambat Wnt/?-Catenin untuk Terapi Pancreatic Ductal Adenocarcinoma

Ramadhan,

Rusli,

Fakih

2023

J. Sains Kes.

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In the pancreatic ductal adenocarcinoma (PDAC) initiation and progression, the Wnt/β-Catenin signaling pathway showed a very important role. Earlier study showed that novel phenyl benzimidazoles have inhibiton activity in Wnt/?-Catenin pathway. The purpose of the present study was to design novel phenyl benzimidazoles as a Wnt/?Catenin inhibitor on PDAC based on the Quantitative In the pancreatic ductal adenocarcinoma (PDAC) initiation and progression, the Wnt/?-Catenin signaling pathway showed a very important role. Earlier study showed that novel phenyl benzimidazoles have inhibiton activity in Wnt/?-Catenin pathway. The purpose of the present study was to design novel phenyl benzimidazoles as a Wnt/?Catenin inhibitor on PDAC based on the Quantitative Structure Activity Relationship (QSAR) method. The molecule structures were built optimized by semi empirical AM1 using Gaussian. 12 Descriptors were selected which represented electronical, hydrophobic, and steric parameters using MOE 2014.0901. The compounds suspected as an outlier were then removed from the data set based on XZ-score value, i.e. compounds with XZ-score above 2.5. The data set were then classified into two parts, i.e. training set and test set. Validation was performed using Leave One Out (LOO) method and F test. The new derivatives were designed using topliss scheme, in which parent compound with the lowest IC value was used as a 50 template. The statistical analysis showed that there were two most influential descriptors of Wnt/?-Catenin inhibition activity: mr and LogS. The LOO validation gave Q2 = 0.7363. Six new derivatives, predicted to have lower IC that of parent compound. Keywords: Benzimidazoles, PDAC, QSAR, Wnt/?-Catenin Abstrak Jalur pensinyalan Wnt/?-Catenin sangat penting dalam inisiasi dan perkembangan dari pancreatic ductal adenocarcinoma (PDAC). Studi sebelumnya menunjukkan bahwa fenil benzimidazol baru memiliki aktivitas penghambatan di jalur Wnt/?-Catenin. Tujuan dari penelitian ini adalah untuk merancang fenil benzimidazol baru sebagai penghambat Wnt/?Catenin pada PDAC berdasarkan metode Hubungan Kuantitatif Struktur-Aktivitas (HKSA). Struktur molekul dibangun dan dioptimalkan dengan metode AM1 semi empiris menggunakan Gaussian. Sebanyak 12 Deskriptor dipilih yang mewakili parameter elektronik, hidrofobik, dan sterik menggunakan MOE 2014.0901. Senyawa-senyawa yang diduga outlier kemudian dikeluarkan dari kumpulan data berdasarkan nilai XZ-score, yaitu senyawa-senyawa dengan XZ-score di atas 2,5. Kumpulan data kemudian diklasifikasikan menjadi dua bagian, yaitu training set dan test set. Validasi dilakukan menggunakan metode statistik Leave One Out (LOO). Turunan baru dirancang menggunakan skema topliss, dimana senyawa induk dengan nilai IC terendah digunakan sebagai template. Analisis statistik menunjukkan bahwa ada dua deskriptor paling berpengaruh dari aktivitas penghambatan Wnt/?-Catenin: mr dan LogS. Validasi LOO menunjukkan niali Q2 = 0,7363. Enam turunan baru, diprediksi memiliki IC yang lebih rendah dari senyawa induknya. Kata Kunci: Benzimidazoles, PDAC, HKSA, Wnt/?-Catenin

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From the Manual Method of Topliss to a Modified Quantitative Method

Cited by 2 publications

References 11 publications

Optimized Modified Topliss Method: A Tool for Quantitative Structure-Activity Relationship Studies

Optimized Modified Topliss Method: A Tool for Quantitative Structure-Activity Relationship Studies

Hubungan Kuantitatif Struktur-Aktivitas dan Desain Senyawa Novel Phenyl Benzimidazoles sebagai Penghambat Wnt/?-Catenin untuk Terapi Pancreatic Ductal Adenocarcinoma

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