Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

Abstract

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2.

Identification of Novel Natural Dual HDAC and Hsp90 Inhibitors for Metastatic TNBC Using e-Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Studies

“…A library containing 270,540 natural product structures was obtained from the ZINC database ( accessed on 25 May 2022), then, using the MacroModel tool with the default parameters [ 62 ], the library was subjected to energy minimization under the OPLS4 force field to ensure that the compounds’ structures were acceptable for further computational calculations.…”

“…The top compounds according to the docking score were also analyzed to predict their pharmacokinetic properties by the QikProp tool of Schrödinger [ 62 ]. This initial prediction may be useful in decreasing the failure probability in the future stages of drug development.…”

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

“…This process generated a grid file representing the site on the receptor where the ligand docking would occur. The receptor grid generation panel in Maestro was utilized to configure the grid generation job ( Mohamed et al, 2022 ). The ligand molecule that bound to the TrkA allosteric site was identified and excluded from the grid generation process.…”

MNK Proteins as Therapeutic Targets in Leukemia

“… 7 One study used extensive in silico analysis to identify three natural compounds from the ZINC database that had high affinity and stable interaction to MNK2 and PIM2 which they suggested as potential therapeutics in AML. 95 Usnic acid derivatives were demonstrated to reduce p-eIF4E as well as to target pan PIMs in K562 and HL-60 leukemia cells. 76 Although it was not found that MNK was directly inhibited, the reduction to MNK/eIF4E signaling in combination with the PIM inhibition by these compounds further shows the efficacy in targeting these two axes.…”