Activity

Approximately 40-50% of patients with cutaneous melanoma harbor point mutations in

. BRAF and MEK inhibitors in combination are now a standard therapy for advanced

-mutated melanoma. Nevertheless, survival rates with the combination are limited, highlighting the need for further therapeutic improvement and strategies to overcome primary and acquired resistance.

Encorafenib, a highly selective BRAF inhibitor, was developed in combination with binimetinib, a potent, selective allosteric MEK1/2 inhibitor, to improve efficacy and tolerability over other approved combo-targeted therapies. This novel combination shows peculiar pharmacodynamic properties which translate in a higher on-target potency and paradox index. Consistent survival improvements for encorafenib and binimetinib in

-mutated melanoma have been confirmed in clinical trials, with over 4years of median follow up.

the favorable survival results and the attractive toxicity profile suggest that encorafenib and binimetinib combination is an intriguing standard option when targeted therapies are considered as first line treatment in BRAF mutated melanoma patients. In the near future, results from ongoing clinical trials will provide information on the use of this novel combination in specific situation, including as adjuvant treatment or as a combination strategy.

the favorable survival results and the attractive toxicity profile suggest that encorafenib and binimetinib combination is an intriguing standard option when targeted therapies are considered as first line treatment in BRAF mutated melanoma patients. In the near future, results from ongoing clinical trials will provide information on the use of this novel combination in specific situation, including as adjuvant treatment or as a combination strategy.We present a dissipative particle dynamics (DPD) model for wax formation (i.e., the freezing transition) in linear and branched alkanes at room temperature (298 K) and atmospheric pressure. We parametrize the model using pure liquid phase densities and the onset of wax formation as a function of alkyl chain length. Significant emphasis is placed on building an accurate representation of the underlying molecular architecture by careful consideration of bond lengths and angles, aided by distributions obtained from molecular dynamics simulation. Using the derived model, we observe wax formation in n-alkanes when the alkyl chain length is greater than 18 (n-octadecane), in excellent agreement with experimental observations. Further, we reproduce the behavior of branched alkanes and mixtures including solubilities of heavy alkanes in light alkane solvents.To obtain accurate and converged free energy calculations for ligand binding to biomolecular systems requires validated force fields and extensive sampling of the energy landscape, which requires exhaustive and effective conformational searching methods. Herein, we introduce the consecutive histograms Monte Carlo (CHMC) sampling protocol that generates receptor-ligand binding modes within a series of continuously distributed sampling units ranging from placement near the geometric center of the receptor’s binding site to fully unbound states. This protocol employs independent energy-state sampling for calculating the ensemble energy within every predefined location along the receptor-ligand dissociation pathway, without the need to traverse the energy barriers as in molecular dynamic simulations during the dissociation procedure. We applied this method to a set of selected receptor targets with their corresponding ligands providing detailed studies of molecular binding free energy predictions. The results show that the CHMC gives an excellent accounting of the free energy surfaces and binding free energies at a reasonable computational cost.We present an ab initio molecular dynamics (MD) investigation of the tautomeric equilibrium for the aqueous solutions of glycine and acetone under realistic experimental conditions. Metadynamics is used to accelerate proton migration among tautomeric centers. Due to the formation of complex water-ion structures involved in the proton dynamics in the aqueous environment, standard enhanced sampling approaches may face severe limitations in providing a general description of the phenomenon. Recently, we have developed a set of collective variables (CVs) designed to study protons transfer reactions in complex condensed systems [Grifoni, E. Proc. Natl. Acad. Sci. U.S.A. ZX703 solubility dmso 2019, 116, 4054 4057]. In this work, we applied this approach to study proton dissociation dynamics leading to tautomeric interconversion of biologically and chemically relevant prototypical systems, namely, glycine and acetone in water. Although relatively simple from a chemical point of view, the results show that even for these small systems, complex reaction pathways and nontrivial conversion dynamics are observed. The generality of our method allows obtaining these results without providing any prior information on the dissociation dynamics but only the atomic species that can exchange protons in the process. Our results agree with literature estimates and demonstrate the general applicability of this method in the study of tautomeric reactions.A major bottleneck in metabolomics is the annotation of a molecular formula as a first step to a tentative structure assignment of known and unknown metabolites. The direct observation of an isotopic fine structure (IFS) provides the ability to confidently assign an unknown’s molecular formula out of a complex mass spectrum. However, the majority of mass spectrometers deployed for metabolomic studies do not have sufficient resolving power and high-fidelity isotope ratios in the mass range of interest to determine molecular formulas from IFS data. To increase the number of unknowns for which IFS can be determined, a segmented “boxcar” approach using a selection quadrupole as a broadband mass filter is used. In this longer, enhanced dynamic range discovery experiment, selected ions in a specific mass range are accumulated before detection by the analyzer cell. The mass filter window is then moved across the entire mass range resulting in a composite mass spectrum covering the m/z range of interest for phenomics research.