Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Abstract

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in NSCLC.

Understanding the P-Loop Conformation in the Determination of Inhibitor Selectivity Toward the Hepatocellular Carcinoma-Associated Dark Kinase STK17B

“…The CC ij matrix of STK17B that is represented by a two-by-two plot of the Cα CC ij coefficients reveals a conserved pattern of correlated/anticorrelated motions in all apo, ADP-bound and ligand-bound states ( Figure 2 ). The N-lobe containing the P-loop (residues 40–47) and C-lobe shows anticorrelated motions, which is also observed on other protein kinases such as anaplastic lymphoma kinase (ALK) ( Liang et al, 2021 ), BCR-ABL ( Zhang et al, 2022a ) and epidermal growth factor receptor (EGFR) ( Qiu et al, 2021 ). This suggests that the opposite movement of the N- and C-lobes favours the “open or closed” conformational transition of the nucleotide binding site underlying ADP/ATP and substrate binding.…”

“…The dynamic correlation analysis was carried out to probe the interdependent dynamics among different kinase domains. Two distinct methods, including the traditional Pearson cross-correlation (CC ij ) and the generalized correlation (GC ij ), were used to calculate the correlation analysis ( Shibata et al, 2020 ; Liang et al, 2021 ; Zhang et al, 2022a ), which was conducted and averaged over all MD trajectories. The CC ij analysis describes the collinear correlation between the two residue Cα atoms ( i and j ), reflecting whether they move in the correlated motions (CC ij > 0) or in the anti-correlated (CC ij < 0) motions.…”

Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A

“…The ΔG nonpolar was calculated using the function of the solvent accessible surface area with a γ value of 0.0072 kcal/(mol∙Å 2 ) and a b value of 0 kcal/mol. Per-residue free energy decomposition of the total ∆G binding was then carried out using the same MM–GBSA setting [ 53 , 54 ].…”

Insights into the Allosteric Effect of SENP1 Q597A Mutation on the Hydrolytic Reaction of SUMO1 via an Integrated Computational Study

“…A two-stage energy minimization approach was performed to optimize the initial complexes using previous protocols [48][49][50]. First, we applied minimization of water molecules and ions (Na + and Cl − ) with positional restraints on protein atoms via a harmonic potential with a force constant of 500 kcal mol −1 Å −2 .…”