4.5 Article

Identification of allosteric inhibitor against AKT1 through structure-based virtual screening

Journal

MOLECULAR DIVERSITY
Volume 27, Issue 6, Pages 2803-2822

Publisher

SPRINGER
DOI: 10.1007/s11030-022-10582-7

Keywords

AKT1 inhibitor; Allosteric binding; Virtual screening; African natural products; Molecular dynamics simulation

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In this study, potential inhibitors targeting AKT1 were found through structure-based virtual screening from a natural compounds library. Molecular docking and simulation analysis revealed that hit 1, hit 2, and hit 5 had better binding affinity, stability, and compactness, and possessed molecular features required for allosteric inhibition.
AKT (serine/threonine protein kinase) is a potential therapeutic target for many types of cancer as it plays a vital role in cancer progression. Many AKT inhibitors are already in practice under single and combinatorial therapy. However, most of these inhibitors are orthosteric / pan-AKT that are non-selective and non-specific to AKT kinase and their isoforms. Hence, researchers are searching for novel allosteric inhibitors that bind in the interface between pH and kinase domain. In this study, we performed structure-based virtual screening from the afroDB (a diverse natural compounds library) to find the potential inhibitor targeting the AKT1. These compounds were filtered through Lipinski, ADMET properties, combined with a molecular docking approach to obtain the 8 best compounds. Then we performed molecular dynamics simulation for apoprotein, AKT1 with 8 complexes, and AKT1 with the positive control (Miransertib). Molecular docking and simulation analysis revealed that Bianthracene III (hit 1), 10-acetonyl Knipholonecyclooxanthrone (hit 2), Abyssinoflavanone VII (hit 5) and 8-c-p-hydroxybenzyldiosmetin (hit 6) had a better binding affinity, stability, and compactness than the reference compound. Notably, hit 1, hit 2 and hit 5 had molecular features required for allosteric inhibition.

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