Insights into pralsetinib resistance to the non-gatekeeper RET kinase G810C mutation through molecular dynamics simulations.

OBJECTIVE: RET (rearranged during transfection) kinase, as a transmembrane receptor tyrosine kinase, is a therapeutic target for several human cancer such as non-small cell lung cancer (NSCLC) and thyroid cancer. Pralsetinib is a recently approved drug for the treatment of RET-driven NSCLC and thyroid cancers. A single point mutation G810C at the C-lobe of the RET kinase causes pralsetinib resistance to this non-gatekeeper variant. However, the detailed mechanism remains poorly understood. METHODS: Here, multiple microsecond molecular dynamics (MD) simulations, molecular mechanics/generalized born surface area (MM/GBSA) binding free energy calculations, and community network analysis were performed to reveal the mechanism of pralsetinib resistance to the RET G810C mutant. RESULTS: The simulations showed that the G810C mutation had a minor effect on the overall conformational dynamics of the RET kinase domain. Energetic analysis suggested that the G810C mutation reduced the binding affinity of pralsetinib to the mutant. Per-residue energy contribution and structural analyses revealed that the hydrogen bonding interactions between pralsetinib and the hinge residues Glu805 and Ala807 were disrupted in the G810C mutant, which were responsible for the decreased binding affinity of pralsetinib to the mutant. CONCLUSIONS: The obtained results may provide understanding of the mechanism of pralsetinib resistance to the non-gatekeeper RET G810C mutant.

How does nintedanib overcome cancer drug-resistant mutation of RET protein-tyrosine kinase: insights from molecular dynamics simulations.

Targeted drug therapies represent a therapeutic breakthrough in the treatment of human cancer. However, the emergence of acquired resistance inevitably compromises therapeutic drugs. Rearranged during transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase, is a target for several kinds of human cancer such as thyroid, breast, and colorectal carcinoma. A single mutation L881V at the RET kinase domain was found in familial medullary thyroid carcinoma. Nintedanib can effectively inhibit the RET L881V mutant, whereas its analog compound 1 is unable to combat this mutant. However, the underlying mechanism was still unexplored. Here, molecular dynamics (MD) simulations, binding free energy calculations, and structural analysis were performed to uncover the mechanism of overcoming the resistance of RET L881V mutant to nintedanib. Energetic analysis revealed that the L881V mutant remained sensitive to the treatment of nintedanib, whereas it was insensitive to the compound 1. Structural analysis further showed that the distribution of K758, D892, and N879 network had a detrimental effect on the binding of compound 1 to the L881V mutant. The obtained results may provide insight into the mechanism of overcoming resistance in the RET kinase.

Achieving Rich Mixed-Valence Polysulfide/Carbon Nanotube Films toward Ultrahigh Volume Energy Density and Largely Deformable Pseudocapacitors.

In this work, new insights into dependence of electrochemical performance enhancement on transition metals' rich mixed valence and their atomic ratio as well as redox active polysulfides are proposed. Especially, the influence of atomic ratio is further demonstrated by both experiments and density functional theoretical calculation where increasing Co/S leads to the enlargement of both interatom distance and hole diameter in a MnxCoySz cell. We rationally designed and prepared novel flexible electrodes of a rich mixed-valence polysulfide MnxCoySz/carbon nanotube film (CNTF) through acid activation of a dense CNTF into a hydrogel-like conductive matrix, growth of the MnxCoy(CO3)0.5OH precursor on each CNT, and controlled sulfidation. Nanostructure control allows us to obtain fast electron/ion transfer and increased availability of active sites/interfaces. The optimal MnCo9S10/CNTF shows a specific capacitance reaching 450 F cm-3 at 10 mA cm-2, much higher than reported values for CNT-based electrodes. Also, it exhibits remarkable cycling stability with only 1.6% capacity loss after 10 000 cycles at a high current density of 80 mA cm-2. An all-solid-state asymmetric supercapacitor (ASC) applying MnCo9S10/CNTF delivers an exceptionally high volumetric energy density of 67 mW h cm-3 (at 10 W cm-3). Particularly, integrated electric sources with adjustable output voltages can be obtained by connecting several ASCs in series, and there are no structural failure and capacity loss during repeated large-angle twisting and vigorous hammering. This work provides a general route to energy storage devices with ultrahigh volumetric energy density and outstanding reliability for wearable electronics.