Fungal secondary metabolites as a potential inhibitor of T315I- BCR::ABL1 mutant in chronic myeloid leukemia by molecular docking, molecular dynamics simulation and binding free energy exploration approaches

Abstract

Background: Chronic Myeloid Leukemia (CML) is particularly challenging to treat due to the T315I BCR::ABL1 mutation. Although fungal metabolites are known for their pharmaceutical potential, none are approved for CML. Our study screened approximately 2000 fungal secondary metabolites to discover inhibitors targeting the T315I- BCR::ABL1 mutant protein.

Methods: We conducted comprehensive analyses to elucidate the interactions between the T315I-BCR::ABL1 mutant protein and selected fungal metabolites. These analyses included molecular docking, ADMET assessment, molecular dynamics simulations, principal components analysis, exploration of free energy landscapes, and per-residue decomposition.

Results: We identified a range of binding affinities for fungal secondary metabolites, from -11.2 kcal/mol to -2.90 kcal/mol, with the co-crystal ponatinib showing a binding affinity of -9.9 kcal/mol. Notably, twenty seven fungal metabolites had affinities ≤ -10.0 kcal/mol, surpassing ponatinib. Eight compounds, including Phellifuropyranone A and Meshimakobnol B, showed favorable drug-likeness. Molecular dynamics parameters, including RMSD, RMSF, Rg, and SASA, confirmed that Phellifuropyranone A and Meshimakobnol B bind stably to the T315I-BCR::ABL1 mutant protein. Additionally, PCA, DCCM, and free energy landscapes analyses validated the consistency of the molecular dynamics parameters. MM/PBSA analysis indicated that Phellifuropyranone A (-22.88 ± 4.28 kcal/mol) and Meshimakobnol B (-25.86 ± 3.51 kcal/mol) bind similarly to ponatinib (-25.54 ± 6.31 kcal/mol). Per-residue decomposition explored residues MET290, VAL299, ILE315, and PHE359 as crucial for binding to the T315I-BCR::ABL1 mutant protein.

Conclusions: Phellifuropyranone A and Meshimakobnol B show significant potency as inhibitors of the T315I-BCR::ABL1 mutant protein, comparable to ponatinib. These compounds may serve as effective alternatives or synergistic agents with ponatinib, potentially overcoming drug resistance and improving treatment outcomes in Chronic Myeloid Leukemia.

Keywords: Chronic myeloid leukemia; Fungal metabolites; Meshimakobnol B; Phellifuropyranone A; T315I-BCR::ABL1.

Fig. 1

Identification of Binding residues of T315I- BCR::ABL1 Mutant Protein. A. Exploring the amino acid residues in the top-ranked binding pocket by PrankWeb tool. B. Exploration of binding residues with Ponatinib in co-crystal structure of T315I-BCR::ABL1 mutant protein.

Fig. 2

The 3-dimensional interactions of 8 drug-like fungal secondary metabolites with the T315I- BCR::ABL1 mutant protein.

Fig. 3

The 2-dimensional interactions of 8 drug-like fungal secondary metabolites with the T315I- BCR::ABL1 mutant protein.

Fig. 4

The comparative RMSD (A) and RMSF (B) plots for Mutant protein-Phellifuropyranone A, Mutant protein-(+)-(R)-grifolinone C, Mutant protein-Meshimakobnol B, and Mutant protein-Ponatinib complex.

Fig. 5

The comparative Rg (A) and SASA (B) plots for Mutant protein-Phellifuropyranone A, Mutant protein-(+)-(R)-grifolinone C, Mutant protein-Meshimakobnol B, and Mutant protein-Ponatinib complex.

Fig. 6

The dynamics of intermolecular hydrogen bonds between the mutant protein and lead fungal metabolites. A. Number of hydrogen bond between Protein and Phellifuropyranone A. B. Number of hydrogen bond between protein and (+)-(R)-grifolinone C. C. Number of hydrogen bond between protein and meshimakobnol B. D. Number of hydrogen bond between protein and ponatinib.

Fig. 7

Principal component analysis. 2-diensional projection of trajectories into the top three eigenvectors (PC1, PC2, and PC3) for a mutant protein in complex with Phellifuropyranone A (A), (+)-(R)-grifolinone C (B), Meshimakobnol B (C), and Ponatinib (D). The red dots and blue dots stood for the stable state. And the intermediate state among these two states was shown by light red or light blue dot. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 8

DCCM plots for (A) Mutant protein-Phellifuropyranone A, (B) Mutant protein-(+)-(R)-grifolinone C, (C) Mutant protein-Meshimakobnol B, and (D) Mutant protein-Ponatinib complex.

Fig. 9

Porcupine analysis for (A) Mutant protein-Phellifuropyranone A, (B) Mutant protein-(+)-(R)-grifolinone C, (C) Mutant protein-Meshimakobnol B, and (D) Mutant protein-Ponatinib complex of PC1. The red spikes represent the direction of fluctuations presented by PC1, and their size represents the magnitude of the fluctuation observed in the Cα atom backbone of the protein. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 10

Free energy landscape in three dimensional and two dimensional representations for (A-B) Mutant protein-Phellifuropyranone A, (C-D) Mutant protein-(+)-(R)-grifolinone C, (E-F) Mutant protein-Meshimakobnol B, and (G-H) Mutant protein-Ponatinib complex.

Fig. 11

Calculated Energies in kcal/mol and its Components Using MM-PBSA Method Obtained from the whole trajectory analysis. The energy calculation plot for (A) Mutant protein-Phellifuropyranone A, (B) Mutant protein-(+)-(R)-grifolinone C, (C) Mutant protein-Meshimakobnol B, and (D) Mutant protein-Ponatinib complex.

Fig. 12

Binding free energy plot for (A) Mutant protein-Phellifuropyranone A, (B) Mutant protein-(+)-(R)-grifolinone C, (C) Mutant protein-Meshimakobnol B, and (D) Mutant protein-Ponatinib complex.

Fig. 13

Residue wise binding free contribution energy for A) Mutant protein-Phellifuropyranone A, (B) Mutant protein-(+)-(R)-grifolinone C, (C) Mutant protein-Meshimakobnol B, and (D) Mutant protein-Ponatinib complex.