Design of Inhibitors That Target the Menin–Mixed-Lineage Leukemia Interaction
Date
2023
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Computation
Abstract
The prognosis of mixed-lineage leukemia (MLL) has remained a significant health concern.
especially for infants. The minimal treatments available for this aggressive type of leukemia has
been an ongoing problem. Chromosomal translocations of the KMT2A gene are known as MLL.
which expresses MLL fusion proteins. A protein called menin is an important oncogenic cofactor
for these MLL fusion proteins, thus providing a new avenue for treatments against this subset of
acute leukemias. In this study, we report results using structure-based drug design (SBDD)
approach to discovering potential novel MLL-mediated leukemia inhibitors from natural products
against menin. The three-dimensional (3D) protein model was derived from Protein Databank
(Protein ID: 4GQ4), and EasyModeller 4.0 and I-TASSER were used to fix missing residues during
rebuilding. Out of the ten protein models generated (five from EasyModeller and I-TASSER each),
One model was selected. The selected model demonstrated the most reasonable quality and had 75.5%
of residues in the most favored regions, 18.3% of residues in additionally allowed regions, and 3.3% of
residues in generously allowed regions, and 2.9% of residues in disallowed regions. A ligand library
containing 25,131 ligands from a Chinese database was virtually screened using AutoDock Vina, in
addition to three known menin inhibitors. The top 10 compounds, including ZINC000103526876,
ZINC000095913861, ZINC000095912705, ZINC000085530497, ZINC000095912718, ZINC000070451048,
ZINC000085530488, ZINC000095912706, ZINC000103580868, and ZINC000103584057 had binding
energies of −11.0, −10.7, −10.6, −10.2, −10.2, −9.9, −9.9, −9.9, −9.9, and −9.9 kcal/mol, respectively.
To confirm the stability of the menin-ligand complexes and the binding mechanisms, molecular
dynamics simulations, including molecular mechanics and Poisson-Boltzmann surface area (MM/PBSA)
computations were performed. The amino acid residues that were found to be potentially crucial in
ligand binding included Phe243, Met283, Cys246, Tyr281, Ala247, Ser160, Asn287, Asp185, Ser183,
Tyr328, Asn249, His186, Leu182, Ile248, and Pro250. MI-2-2 and PubChem CIDs 71777742 and 36294
were shown to possess anti-menin properties; thus, this justifies a need to experimentally determine
the activity of the identified compounds. The compounds identified herein were found to have good pharmacological profiles and negligible toxicity. Additionally, these compounds were
predicted as antileukemic, antineoplastic, chemopreventive, and apoptotic agents. The 10 natural
compounds can be further explored as potential novel agents for the effective treatment of MLL-mediated leukemia.
Description
Research Article
Keywords
computer-aided drug design, molecular dynamics, mixed-lineage leukemia