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. 2018 Dec 9;14(9):499-503.
doi: 10.6026/97320630014499. eCollection 2018.

Molecular screening and docking analysis of LMTK3and AKT1 combined inhibitors

Loubna Allam  1   2 , Ghrifi Fatima  1 , Lakhlili Wiame  1 , El Amri Hamid  2 , Ibrahim Azeddine  1
Affiliations

Molecular screening and docking analysis of LMTK3and AKT1 combined inhibitors

Loubna Allam et al. Bioinformation. .

Abstract

The abnormal activation of AKT/mTOR signaling pathway and overexpression of LMTK3, are the main factors involved in the generation of drug resistance. Therefore, the use of computer-aided drug design in the inhibitors discovery offers an advantage to provide new candidates for the treatment of this resistance. We realised the virtual screening and molecular docking of AKT1 and LMTK3 proteins by the Dockblaster server. In addition, with abundance of candidates under development for AKT1 kinase, we have also conducted a Quantitative Structure-Activity Relationship (QSAR) study based on these compounds, in order to design more active compounds and predict their activity for development of a new inhibitor of AKT1. QSAR tests were performed for AKT1 using the Partial Least Squares method with a correlation coefficient of R2=0.8062 and a cross-validation of q2=0.6995. This test has selected five compounds as competitive inhibitors-AKT1-ATP with a better biological activities. In parallel the molecular screening has selected five other compounds as competitive ATP-inhibitors of LMTK3. One of them is a common inhibitor with AKT1, and it is marketed as a moderate to severe pain therapy. The ADME predictions confirmed the inhibitors pharmacological activity of these compounds for potential consideration as drug candidates.

Keywords: AKT1; ATP-inhibitors; LMTK3; QSAR; Virtual screening.

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Figures

Figure 1
Figure 1
Relationship between observed and predicted data from QSAR model. Notes: the compounds of the model QSAR are represented by dots, those of training set are in blue and those of test set are in red. Abbreviations: Pred, Predict; QSAR, quantitative structure-activity relationship.
Figure 2
Figure 2
Visualization of different interactions between the compound which inhibits both AKT1 and LMTK3 through hydrogen bonds and its localization in the active site of both proteins. The identical compound (numbered n°33 for AKT1 and n�21 for LMK3) interacts with both proteins through three hydrogen bonds of their hinge region of the catalytic site. (A) AKT1 ; (B) LMTK3. Notes: Red areas mean oxygen atom, blue areas mean nitrogen atom, and green areas mean other. The dotted yellow line represents the bonds. The numbers represent the size of the hydrogen bonds established between the ligand and the receptor.
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