Cytotoxic monastrol derivatives as adjective inhibitors of drug-resistant Eg5: a molecular dynamics perspective.

The mitotic kinesin Eg5 is a motor protein involved in the formation of bipolar spindle and cell division. Eg5 is overexpressed in various cancer cells and Eg5 targeting agents are promising candidates for cancer therapy. Subsequent to the discovery of monastrol as a small-molecule Eg5 modulator, numerous inhibitors/modulators have been reported from which a few entered clinical trials. Mutagenic investigations specified declined sensitivity of Eg5 allosteric site to monastrol due to the occurrence of drug-resistant mutations in some cell cultures. Accordingly, identification of tight binders to the mutant Eg5 allosteric site is an invaluable strategy to devise more efficient Eg5 modulators. We have previously synthesized a few dihydropyrimidinethione (DHPMT)-based 5-carboxamide monastrol derivatives (1-5) with higher cytotoxicities against AGS (IC50 9.90-98.48 µM) and MCF-7 (IC50 15.20-149.13 µM) cancer cell lines than monastrol. Within a current study, a structural insight was offered into the binding mechanism of intended derivatives inside the mutant Eg5 loop5/α2/α3 allosteric pocket. Molecular docking of the DHPMT R and S-enantiomers unraveled top-scored Eg5 complexes. Molecular dynamics (MD) simulations were carried out on 5 superior complexes as (R)-2/D130V-Eg5, (R)-4/D130V-Eg5, (R)-5/D130V-Eg5, (R)-5/L214I-Eg5, (R)-5/R119L-Eg5, and the control groups monastrol/D130V-Eg5, monastrol/L214I-Eg5, monastrol/R119L-Eg5. Free energy calculations were conducted through conformational sampling of MD-driven binding trajectories. Our results provided structural details on probable interaction mechanism of the cytotoxic DHPMTs that are difficult to address experimentally. The outputs of the current study propose new monastrol derivatives as probable resistance-overwhelming Eg5 modulators.Communicated by Ramaswamy H. Sarma.

MD simulations revealed that R-enantiomer of 5 overwhelmed drug-resistant D130V-Eg5.Induced fit L5 loop conformation led to the accommodation of 5 inside Eg5 allosteric site.Cooperative lipophilic contacts accommodated DHPMTs inside D130V-Eg5 allosteric site.Ser120 pointed toward 5 and made a stable H-bond particularly within the 60-100 ns.Major fluctuations of D130V-Eg5 allosteric pocket occurred at L5 loop upon binding to 5.

Evaluation of solvent effect on the effective interactions of Isotretinoin and Tretinoin: Isomeric forms of vitamin A.

Vitamin A and its derivatives are effective in many medical dermatology treatments. Isotretinoin and Tretinoin, as medication and therapeutic agents, are widely applied in dermatology to treat a variety of skin cancers and disorders. In this regards, solvent as a complex environment can surround solute molecules and change their function. For this reason, the function of medication molecules as solute highly depends on their biochemical structure and the surrounding environment. The main purpose of this study is to investigate the effective interactions between the solvent molecules with Isotretinoin and Tretinoin medications. The evaluation of the spectral characteristics based on Linear Solvation Energy Relationship (LSER) models of Kamlet-Abboud-Taft and Catalán, as well as estimating the dipole moments based on the solvatochromic method were carried out. The findings revealed that specific interactions (solvent acidity and solvent basicity), exert a greater influence than non-specific interactions (polarity/polarizability). According to the dipole moments variations, the Intra-molecular Charge Transfer (ICT) process is possible. Solvent-accessible surfaces provided a better assessment of active group sites. Furthermore, density functional theory (DFT) calculations were used to gain a profound understanding of the experimental results. The insights from this research can be valuable for pharmacists and chemists working on the development of novel medications or practical applications.

Ag-Au bimetallic nanoclusters formed from a homogeneous gas phase: a new thermodynamic expression confirmed by molecular dynamics simulation.

In this work, two probabilistic and thermodynamic limits for formation of a bimetallic nanocluster from a homogeneous gas phase were obtained in order to investigate the related phenomena using molecular dynamics simulation. Therefore, by application of some simple assumptions from thermodynamics and statistical mechanics, a new expression for composition of the nanocluster was derived which depends only on the initial conditions of the system and one adjustable parameter. This expression can be easily fitted to the results of molecular dynamics and can be used as a measure of the thermodynamic contribution in the cluster formation process. Then, molecular dynamics simulations were performed for several systems containing the same total number of metallic atoms and different concentrations of Ag and Au atoms. The results of this study exhibited that depending on different initial compositions of Ag and Au types, fcc and icosahedral structures are formed. Moreover, increase of the initial Ag concentration leads to products whose compositions are more controlled by probability limits. However, longer simulation times indicated that creation of more thermodynamically favoured nanoclusters depends on the formation of more probable ones in the early stages of the simulation.

Polar and low polar solvents media effect on dipole moments of some diazo Sudan dyes.

Absorption and fluorescence spectra of three Sudan dyes (SudanIII, SudanIV and Sudan black B) were recorded in various solvents with different polarity in the range of 300-800nm, at room temperature. The solvatochromic method was used to investigate dipole moments of these dyes in ground and excited states, in different media. The solvatochromic behavior of these substances and their solvent-solute interactions were analyzed via solvent polarity parameters. Obtained results express the effects of solvation on tautomerism and molecular configuration (geometry) of Sudan dyes in solvent media with different polarity. Furthermore, analyze of solvent-solute interactions and value of ground and excited states dipole moments suggests different forms of resonance structures for Sudan dyes in polar and low-polar solvents.

Synthesis, characterization, DFT studies and catalytic activities of manganese(II) complex with 1,4-bis(2,2':6,2''-terpyridin-4'-yl) benzene.

A new di-manganese complex with "back-to-back" 1,4-bis(2,2':6,2''-terpyridin-4'-yl) benzene ligation has been synthesized and characterised by a variety of techniques. The back-to-back ligation presents a novel new mononuclear manganese catalytic centre that functions as a heterogeneous catalysis for the evolution of oxygen in the presence of an exogenous oxidant. We discuss the synthesis and spectroscopic characterizations of this complex and propose a mechanism for oxygen evolution activity of the compound in the presence of oxone. The di-manganese complex also shows efficient and selective catalytic oxidation of sulfides in the presence of H(2)O(2). Density functional theory calculations were used to assess the structural optimization of the complex and a proposed reaction pathway with oxone. The calculations show that middle benzene ring is distorted respect to both of metallic centers, and this in turn leads to negligible resonance of electrons between two sides of complex. The calculations also indicate the unpaired electron located on oxyl-ligand emphasizes the radical mechanism of water oxidation for the system.