Specificity and molecular mechanism of abortificient action of prostaglandins

The paper reports comparison of electrostatic charge and energy distribution on the basis of the CNDO /2 method for six forms of prostaglandins–PGF_2α, PGF_1β, PGE₁, PGE₂, PGB₁, and PGA₁–having diverse physiological action. The isopotential mapping done in three dimension showed that the lower value of electrostatic potential and proximity of the two low energy regions around O₉ and O₁₁ in PGE₂ and PGF_2α is probably responsible for their higher abortificient activity. We also compare here the variation of the long- and short-range interaction between ring–chain and chain–chain portion of different forms and compared them with the variation in their action.     

Ligand-selective inhibition of the interaction of steroid receptor coactivators and estrogen receptor isoforms

Ligand-dependent nuclear hormone receptor (NR) signaling requires direct interaction between NR and the steroid receptor coactivators (SRC). Herein we utilize a library of SRC2 peptidomimetics to select for specific inhibitors of the interaction of SRC2 with the two estrogen receptor (ER) isoforms, ERalpha and ERbeta, in the presence of three different ligands: 17beta-estradiol, diethylstilbesterol, and genistein. The pattern of inhibitor selectivity for each ER isoform varied depending upon which ligand was present, thus demonstrating that the ligands exert unique allosteric effects upon the surface of the SRC binding pocket. Several of the lead compounds are highly (>100-fold) selective for blocking the binding of SRC2 to ERalpha, in preference to ERbeta, in the presence of one ligand and therefore may prove useful for decoupling ERbeta signaling from ERalpha signaling.     

Modulating the structure and properties of cell membranes: the molecular mechanism of action of dimethyl sulfoxide

Dimethyl sulfoxide (DMSO) is a small amphiphilic molecule which is widely employed in cell biology as an effective penetration enhancer, cell fusogen, and cryoprotectant. Despite the vast number of experimental studies, the molecular basis of its action on lipid membranes is still obscure. A recent simulation study employing coarse-grained models has suggested that DMSO induces pores in the membrane (Notman, R.; Noro, M.; O'Malley, B.; Anwar, J. J. Am. Chem. Soc. 2006, 128, 13982-13983). We report here the molecular mechanism for DMSO's interaction with phospholipid membranes ascertained from atomic-scale molecular dynamics simulations. DMSO is observed to exhibit three distinct modes of action, each over a different concentration range. At low concentrations, DMSO induces membrane thinning and increases fluidity of the membrane's hydrophobic core. At higher concentrations, DMSO induces transient water pores into the membrane. At still higher concentrations, individual lipid molecules are desorbed from the membrane followed by disintegration of the bilayer structure. The study provides further evidence that a key aspect of DMSO's mechanism of action is pore formation, which explains the significant enhancement in permeability of membranes to hydrophilic molecules by DMSO as well as DMSO's cryoprotectant activity. The reduction in the rigidity and the general disruption of the membrane induced by DMSO are considered to be prerequisites for membrane fusion processes. The findings also indicate that the choice of DMSO concentration for a given application is critical, as the concentration defines the specific mode of the solvent's action. Knowledge of the distinct modes of action of DMSO and associated concentration dependency should enable optimization of current application protocols on a rational basis and also promote new applications for DMSO.     

Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various proposed mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations of thioridazine with zwitterionic and negatively charged model lipid membranes. Thioridazine partitions into the interfacial region of membranes and modifies their structural and dynamic properties, however dissimilarly so at the highest membrane-occurring concentration, that appears to be obtainable only for the negatively charged bilayer. We show that the origin of such changes is the drug induced decrease of the interfacial tension, which ultimately leads to the significant membrane expansion. Our findings support the hypothesis that the phenothiazines therapeutic activity may arise from the drug–membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds.     

Molecular mechanism of HIV-1 integrase-vDNA interactions and strand transfer inhibitor action: a molecular modeling perspective

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an essential enzyme for splicing a viral DNA (vDNA) replica of its genome into host cell chromosomal DNA (hDNA) and has been recently recognized as a promising therapeutic target for developing anti-AIDS agents. The interaction between HIV-1 IN and vDNA plays an important role in the integration process of the virus. However, a detailed understanding about the mechanism of this interactions as well as the action of the anti-HIV drug raltegravir (RAL, approved by FDA in 2007) targeting HIV-1 IN in the inhibition of the vDNA strand transfer is still absent. In the present work, a molecular modeling study by combining homology modeling, molecular dynamics (MD) simulations with molecular mechanics Poisson-Boltzmann surface area (MM-PBSA), and molecular mechanics Generalized-Born surface area (MM-GBSA) calculations was performed to investigate the molecular mechanism of HIV-1 IN-vDNA interactions and the inhibition action of vDNA strand transfer inhibitor (INSTI) RAL. The structural analysis showed that RAL did not influence the interaction between vDNA and HIV-1 IN, but rather targeted a special conformation of HIV-1 IN to compete with host DNA and block the function of HIV-1 IN by forcing the 3'-OH of the terminal A17 nucleotide away from the three catalytic residues (Asp64, Asp116, and Glu152) and two Mg(2+) ions. Thus, the obtained results could be helpful for understanding of the integration process of the HIV-1 virus and provide some new clues for the rational design and discovery of potential compounds that would specifically block HIV-1 virus replication.     

Naphthalimides and analogues as antitumor agents: A review on molecular design,bioactivity and mechanism of action

Our research improves the structure diversity of naphthalimide antitumor agents and distinct variances of antitumor targets and mechanism of action.     

Dissecting the molecular recognition of dual lapatinib derivatives for EGFR/HER2

Abnormalities in the expression levels of EGFR/HER2 are found in many different types of human cancer; therefore, the design of dual inhibitors of EGFR/HER2 is a recognized anti-cancer strategy. Some lapatinib derivatives have been previously synthesized by modification at the methylsulfonylethylaminomethylfuryl group and biologically evaluated, demonstrating that the 2i compound shows potent inhibitory activity against EGFR/HER2-overexpressing cancer cells. In the present study, we explored the structural and energetic features that guide the molecular recognition of 2i using various EGFR/HER2 states. Molecular dynamics (MD) simulation with an MMPB(GB)SA approach was used to generate the inactive EGFR/HER2–ligand complexes. Our results corroborate that slight modification of lapatinib contributes to an increase in the affinity of the 2i compound for inactive EGFR/HER2 as compared with lapatinib compound, which is in accordance with experimental results. Comparison with previous results reveals that lapatinib and its derivative bind more strongly to the inactive than the intermediate active-inactive HER2 state. Principal component analysis allowed the observation that coupling of 2i to EGFR/HER2 is linked to a reduction in the conformational mobility, which may also contribute to the improvement in affinity observed for this compound as compared with lapatinib.     

Triphenylene: A versatile molecular receptor

Since the late seventies, the search for new molecular receptors has been constant in perfecting the affinity and selectivity of recognition in different media. At present, a renewed interest in (host:guest) chemistry focuses on the molecular detection of specific targets such as biological, pollutant, toxic or explosive species. This review of triphenylene-based receptors outlines their recent contribution to molecular recognition. Two main structural approaches were investigated to transform a simple triphenylene moiety into a host for neutral aromatic compounds or cations, by tailoring multivalent molecules provided with or without a flatten cavity. The properties of different receptors are presented along with the latest synthetic methods to prepare high-value triphenylenes and the perspectives in the field of sensing. In addition, the role of functionalized triphenylenes in extended (host:guest) systems is illustrated by the main examples of discotic liquid crystals and porous coordination polymers involving this polyaromatic compound.     

Ring-deactivated hydroxyalkylpyrrole-based inhibitors of alpha-chymotrypsin: synthesis and mechanism of action

13C NMR and mass spectrometry studies have been used to demonstrate that the inhibition of alpha-chymotrypsin by N-sulfonylhydroxymethylpyrrole inhibitors (10) is non-covalent. Hydroxyalkylpyrroles in which an electron-withdrawing group (acyl substituent) is introduced at the alternative C2 position have been synthesised and also shown to inactivate alpha-chymotrypsin. SAR studies on this class suggests that the incorporation of phenylalanine at C2 is favoured, however, there is little gain in introducing a hydrophobic substituent at C5.     

Daptomycin structure and mechanism of action revealed

Daptomycin kills otherwise antibiotic-resistant gram-positive pathogens and is the first lipopeptide antibiotic to reach the clinic. Elucidation of its 3D structure and mechanism of action, reported in this issue of Chemistry & Biology, will facilitate the design and engineering of new, potentially life-saving antibiotics.     

Ionic Liquids: Dissecting the Enthalpies of Vaporization

We calculate the heats of vaporisation for imidazolium‐based ionic liquids [C_nmim][NTf₂] with n=1, 2, 4, 6, 8 by means of molecular dynamics (MD) simulations and discuss their behavior with respect to temperature and the alkyl chain length. We use a force field developed recently. The different cohesive energies contributing to the overall heats of vaporisations are discussed in detail. With increasing alkyl chain length, the Coulomb contribution to the heat of vaporisation remains constant at around 80 kJ mol^?1, whereas the van der Waals interaction increases continuously. The calculated increase of about 4.7 kJ mol^?1 per CH₂‐group of the van der Waals contribution in the ionic liquid exactly coincides with the increase in the heats of vaporisation for n‐alcohols and n‐alkanes, respectively. The results support the importance of van der Waals interactions even in systems completely composed of ions.     

Structure and mechanism of action of isopentenylpyrophosphate-dimethylallylpyrophosphate isomerase

We have obtained the three-dimensional X-ray crystallographic structure of a C67A mutant Escherichia coli isopentenylpyrophosphate-dimethylallylpyrophosphate isomerase (EC 5.3.3.2) complexed with the bromohydrin of isopentenylpyrophosphate, at 1.93 A resolution. The overall backbone fold is very similar to that obtained previously for the wild-type enzyme in the presence of a divalent metal cation (Mn2+ or Mg2+). However, in the new structure, there are two metal binding sites, not just one. The first metal binding site is occupied by Mn2+, coordinated to three histidine and two glutamate residues, while the second is occupied by Mg2+, coordinated to two bromohydrin-ligand phosphate oxygens, the carbonyl oxygen of A67, a carboxyl oxygen of E87, and two water molecules. The C3 hydroxyl group of the bromohydrin inhibitor is involved in a short hydrogen bond to the carboxyl group of E116, one of the two Mn-bound glutamates. The structure obtained is consistent with a mechanism of action of the enzyme in which the carboxyl group of E116 protonates the double bond in isopentenylpyrophosphate, forming a carbocation, followed by removal of a C2 proton by the thiolate of C67, in the wild-type enzyme. The inhibition of the enzyme by a wide variety of other potent inhibitors is also readily explained on the basis of the bromohydrin inhibitor structure.