Molecular screening and docking analysis of LMTK3 and AKT1 combined inhibitors

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.

Targeting the GRP78-Dependant SARS-CoV-2 Cell Entry by Peptides and Small Molecules

“…The entry of the virus is a key step that can be targeted by a possible therapeutic strategy opting for the prediction of a molecule capable of causing simultaneous inhibition of the 2 proteins. 34 , 35 Based on the knowledge gained about the SARS-CoV-2 virus, 2 axes of investigation were explored in this study to prevent the translocation of the virus inside host cells. The first was the inhibition of GRP78 recognition by SARS-CoV-2, by targeting both the nucleotide-binding domain (NBD) and SBD of GRP78 with ATP-competitive small molecules and/or peptides.…”

In silicoandinvitroapproaches to evaluate the bioactivity of Cassia auriculata L extracts

“…Allam et al [33] demonstrated that computer‐aided drug design had been exploited to discover novel inhibitors through virtual screening and molecular docking of AKT1 and LMTK3 proteins by Dock Blaster server. To design and develop a novel inhibitor of AKT1, the author has also conducted a quantitative structure–activity relationship based on these compounds.…”

AKT1 Polymorphism (rs10138227) and Risk of Colorectal Cancer in Moroccan Population: A Case Control Study

“…In contrast, they presented an association of LMTK3 rs9989661 in women with Colon Cancer. Design studies of the 3D structure and LMTK3 and AKT1 inhibitors (Allam et al, 2017;Allam et al, 2018) may be useful to block the spread of cancer in patients with CRC.…”