QSAR, docking, ADMET, and system pharmacology studies on tormentic acid derivatives for anticancer activity

Abstract

To explore the anticancer compounds from tormentic acid derivatives, a quantitative structure-activity relationship (QSAR) model was developed by the multiple linear regression methods. The developed QSAR model yielded a high activity-descriptors relationship accuracy of 94% referred by regression coefficient (r = .94) and a high activity prediction accuracy of 91%. The QSAR study indicates that chemical descriptors, chiV5, T_T_Cl_7, T_2_T_4, SsCH3count, and Epsilon3 are significantly correlated with anticancer activity. This validated model was further been used for virtual screening and thus identification of new potential breast cancer inhibitors. Lipinski's rule of five, ADMET risk and synthetic accessibility are used to filter false positive hits. Filtered compounds were then docked to identify the possible target binding pocket, to obtain a set of aligned ligand poses and to prioritize the predicted active compounds. The scrutinized compounds, as well as their metabolites, were predicted and analyzed for different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Finally, the top-ranked compound NB-12 was evaluated by system pharmacology approach. Later studied the metabolic networks, disease biomarker networks, pathway maps, drug-target networks and generate significant gene networks. The strategy applied in this research work may act as a framework for rational design of potential anticancer drugs.

Theoretical and Insilco Pharmacokinetic Investigations on Some Phenyl Piperidine Derivatives as Novel Antidepressant Agents

“…More so, most of the compounds had leverage lower than the warning h* value of 0.4, a good indication of an appreciably high applicability domain of the model. Furthermore, the computed Euclidean normalized mean distance scores for both the training set and test set compounds (Supplementary Table S2a and b) are found to be within the threshold boundaries of 0-1, showing that all the compounds (training set and test set) were fell within the acceptable domain of applicability (Alam & Khan, 2018). The results reported so far showed that the derived QSAR model displayed a good quality assurance for bioinformatic application of the model as a screen tool (Tropsha et al, 2003).…”

“…The plot of standardized residual against predicted pIC50 of the compounds (Figure 4) shows that the model lack systematic error as the propagation of residuals was observed on both sides of zero (Adedirin, Uzairu, Shallangwa, & Abechi, 2018). The other statistical validation parameters (Table 1, 3, 4 ) like t-statistics (t-test >2), Chi-squared (X 2 = 0.0036) and Root-mean squared error (RMSE= 0.168) for error checking, Variance Inflation Factor (VIF<10) to check for possible multi-collinearity among the descriptors and coefficient of determination for -randomization (cR 2 p= 0.763) to evaluate the robustness of the model are within the threshold limits and also statistically significant (Alam & Khan, 2018). The estimated value of VIF is less than 10 for each of the descriptors, the maximum correlation coefficient between a pair of descriptors is less than 0.7 and the coefficient of determination for -randomization is greater than 0.5 with low R 2 and Q 2 values.…”

Antihypertensive Effect of a Novel Angiotensin II Receptor Blocker Fluorophenyl Benzimidazole: Contribution of cGMP, Voltage-dependent Calcium Channels, and BKCa Channels to Vasorelaxant Mechanisms

“…Hydrogen atoms were added before the processing. Protein coordinates from the crystal structure of the targets were considered for the docking experiment (Alam and Khan, 2018). For the docking and visualization studies, the LibDock program of Discovery Studio version 3.5 (Accelrys, United States, 2013) was used (Alam and Khan, 2019) where protein site features were referred to as hot spots and were of two types (polar and nonpolar).…”

The Effects of Tormentic Acid and Extracts from Callistemon citrinus on Candida albicans and Candida tropicalis Growth and Inhibition of Ergosterol Biosynthesis in Candida albicans

“…Studies have shown that Callistemon citrinus has antimicrobial effects [ 14 – 16 ]. Several phytochemicals have been isolated from the plant including the pentacyclic triterpene and tormentic acid [ 17 ]. Tormentic acid is a triterpene found in a variety of plants.…”

“…Phytochemical studies on C . citrinus seem to also suggest that terpenoids including tormentic acid are responsible for the antifungal activity exhibited by its extracts [ 17 ]. To the best of our knowledge, no studies have been done to investigate the effect of tormentic acid on ergosterol biosynthesis.…”