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  • are the squared cross validation coefficients for leave one

    2024-04-12

    are the squared cross-validation coefficients for leave-one-out, bootstrapping and leave group out respectively. R2 is the squared correlation coefficient, is the adjusted R2 and F is Fisher F-statistic. All values in parentheses are standard deviations. The prediction results which were obtained by the generated model to predict the test set compounds are given in Table 1. As it can be seen from Table 1, the pIC50 values lie in good agreement in comparison with the experimental data. The predicted values of pIC50 have been plotted versus the experimental values by using Eq. (1). The result is shown in Fig. 2. The ability of the built model was verified by using squared cross-validation coefficients for leave-one-out and leave-group-out. , and used to avoid the over fitting and over estimate of the model, and also internal predictive ability of the generated model was verified by using the bootstrap procedure which is highly recommended for QSAR modeling. The robustness of built model was established by high in which based on bootstrapping repeated 5000 times. The value for each parameter of , and is given in Eq. (1). The high values for these parameters confirm the high ability of the model in internal validation. Also, the value of 0.787 for the test set shows the external predictive ability of the built model. The predictive ability and robustness of the model were evaluated using the Y-randomization test [48]. The dependent variable vector (pIC50) was shuffled randomly and the built model after several replications showed to have less R2 and values (Table 3). The obtained result of Table 3 confirms that the good statistical results Eq. (1) are not obtained due to chance. The Williams plot for the created model is given in Fig. 3. The leverage values can be calculated for every Metaphit receptor and plotted vs. standardized residuals, and it allows a graphical detection of both the outliers and the influential chemicals in a model [49]. The influence of compounds on model can be given when the leverage value is greater than warning leverage (in this case h∗=0.7) [50]. This plot shows that the leverage values are less than the warning value of 0.7. Also, from Fig. 3, it is obvious that there are no outlier compounds with standard residuals >3δ for both the training and test sets. All results confirm that the build model is a valid model and can be utilized to predict the ACK1 inhibition activity.
    Conclusion
    Acknowledgments
    Introduction Upon ligand binding, the epidermal growth factor (EGF) receptor (EGFR) is dimerized and autophosphorylated. This results in recruitment and phosphorylation of intracellular substrates (for review see [1], [2]). Activation also induces ubiqutination and endocytosis of the EGFR, and the endocytosis depends on clathrin, as well as Grb2 and the ubiquitin ligase Cbl [3], [4], [5]. Ubiquitinated EGFR is sorted in early endosomes to inner vesicles of multivesicular bodies (MVBs) and further to lysosomes for degradation, while nonubiquitinated EGFR is recycled to the plasma membrane [6], [7], Metaphit receptor [8], [9]. Activated Cdc42-associated kinase (Ack) is often over-expressed in human cancers, and over-expression was found to correlate with poor prognosis [10]. The human Ack protein is encoded by the TNK2 gene and is called Ack1 (hAck1). There are several isoforms of Ack1. Isoform 1 has a molecular weight of approximately 114 kDa and is the best characterized isoform. Throughout this manuscript, Ack1 refers to isoform 1 of Ack1. Ack1 is a nonreceptor protein tyrosine kinase, which can be activated upon stimulation of the EGFR. Additionally, Ack1 has been found to be recruited to the EGFR following EGF stimulation [11], and it has been demonstrated that activation of Ack1 by EGF depends on Grb2 [12]. The Ralt homology domain of Ack1 has been proposed to mediate binding to the EGFR [13], [14], [15], and Ack1 has been assumed to be involved in clathrin-mediated endocytosis due to its ability to bind clathrin, its co-localization with clathrin and AP-2 and its localization to clathrin-containing vesicles [16]. In transfected cells expressing moderate amounts of either wild type or kinase dead Ack1, endocytosis of the transferrin receptor (TfR) was increased, while in cells expressing high levels of Ack1, clathrin aggregates and blocked endocytosis of the TfR was observed [16]. Recently, Ack1 was shown to be important for degradation of the EGFR in mouse cells, and a ubiquitin associated (UBA) domain in murine Ack1 (mAck1) was proposed to be important for the function of mAck1 in EGFR degradation [15].