The structure of ferrudiol. A highly oxidized constituent of uvaria ferruginea

Using spectroscopic and chemical methods, the title compound has been shown to posses stereostructure $\text{1}$ or its mirror image.     

SODOCK: swarm optimization for highly flexible protein-ligand docking

Protein-ligand docking can be formulated as a parameter optimization problem associated with an accurate scoring function, which aims to identify the translation, orientation, and conformation of a docked ligand with the lowest energy. The parameter optimization problem for highly flexible ligands with many rotatable bonds is more difficult than that for less flexible ligands using genetic algorithm (GA)-based approaches, due to the large numbers of parameters and high correlations among these parameters. This investigation presents a novel optimization algorithm SODOCK based on particle swarm optimization (PSO) for solving flexible protein-ligand docking problems. To improve efficiency and robustness of PSO, an efficient local search strategy is incorporated into SODOCK. The implementation of SODOCK adopts the environment and energy function of AutoDock 3.05. Computer simulation results reveal that SODOCK is superior to the Lamarckian genetic algorithm (LGA) of AutoDock, in terms of convergence performance, robustness, and obtained energy, especially for highly flexible ligands. The results also reveal that PSO is more suitable than the conventional GA in dealing with flexible docking problems with high correlations among parameters. This investigation also compared SODOCK with four state-of-the-art docking methods, namely GOLD 1.2, DOCK 4.0, FlexX 1.8, and LGA of AutoDock 3.05. SODOCK obtained the smallest RMSD in 19 of 37 cases. The average 2.29 A of the 37 RMSD values of SODOCK was better than those of other docking programs, which were all above 3.0 A.     

Unexpected domino ring closure: highly stereoselective construction of a tetracyclic indole alkaloid ring system

An unexpected highly stereoselective domino ring closure gave the tetracyclic indole alkaloid IV-2 in good yield in one hydrogenation step.     

Pinastric acid revisited: a complete NMR and X-ray structure assignment

Chemical investigation of a terrestrial lichen has yielded the pulvinic acid derivative pinastric acid (4). The structure of 4 was secured by detailed spectroscopic analysis as well as via a single X-ray diffraction study. This is the first report of the X-ray structure and 2D NMR assignment of pinastric acid (4). Pinastric acid (4) displayed antitumour, antiviral and antimicrobial (both antibacterial and antifungal) activities. Whilst the antiviral and antimicrobial activities are consistent with previous findings of 4 this is the first report of the antitumour properties for the compound.     

Automated docking of highly flexible ligands by genetic algorithms: a critical assessment

An improved version of the fragment-based flexible ligand docking approach SEED-FFLD is tested on inhibitors of human immunodeficiency virus type 1 protease, human alpha-thrombin and the estrogen receptor beta. The docking results indicate that it is possible to correctly reproduce the binding mode of inhibitors with more than ten rotatable bonds if the strain in their covalent geometry upon binding is not large. A high degree of convergence towards a unique binding mode in multiple runs of the genetic algorithm is proposed as a necessary condition for successful docking.     

Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide ‘tail’ to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q ² value of 0.85 and a r ² of 0.94. Results from the docking simulations and the interpretation from QSAR “coeff*stdev” contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.     

Synthesis,biological evaluation and molecular docking study of pyrimidine based thiazolidinone derivatives as potential anti-urease and anti-cancer agents

Hybrid analogs containing molecules are always the choice of different synthetic researcher due to their diverse biological applications and significantly more efficient. Heterocyclic being a good inhibitors against varied disease are most commonly used in drug designing and development. The current study also addressed the synthesis of pyrimidine-based thiazolidinone derivatives (1–13) using stepwise processes and their structure was confirmed using various characterization techniques such as ¹HNMR, ¹³CNMR, and HREI-MS. Furthermore, the biological significances of the synthesized scaffolds were also explored and proved to be as anti-urease and anti-cancer moieties. Their inhibitory potentials were determined using the minimum inhibitory concentration (MIC) in the presence of their standard drugs, Thiourea (IC₅₀ = 8.20 ± 0.20 µM) and Tetrandrineb (IC₅₀ = 12.30 ± 0.10 µM) respectively. Structure activity relationship (SAR) was established for all the synthesized scaffolds and compared their inhibitory potentials in which scaffolds 3 (IC₅₀ = 2.30 ± 0.30 and 3.20 ± 0.50 µM), 6 (IC₅₀ = 3.10 ± 0.20 and 6.20 ± 0.10 µM), 7 (IC₅₀ = 3.20 ± 0.20 and 3.80 ± 0.30 µM) and 10 (IC₅₀ = 4.20 ± 0.20 and 5.10 ± 0.30 µM) exhibited the most influential activity. These compounds were subsequently examined using molecular docking experiments, which evaluate the binding interaction of ligands with enzyme active sites.     

Complexes of a cationic polymer with oxidized anionic liposomes: Composition,structure, and properties

Formation of complexes obtained by the adsorption of a cationic polymer, poly(N-ethyl-4-vinylpyridium bromide), with a degree of polymerization of 600 on the surface of 50-nm bilayer vesicles (liposomes) formed from neutral phosphatidyl choline, anionic diphosphatidyl glycerol (cardiolipin), and a surfactant with one alkyl radical, such as electroneutral n-hexadecylphosphocholine, palmitic acid, or heptanoic acid, is studied. The incorporation of these surfactants into the liposomal membrane stimulates the appearance of oxidized forms of lipids in it. The incorporation of n-hexadecylphosphocholine into the membrane of n-hexadecylphosphocholine and palmitic acid with the alkyl radical, whose length is comparable with the length of alkyl radicals in a lipid molecule, has no effect on the permeability of the membrane. However, these liposomes lose integrity upon the adsorption of polycation; as a result, complexation becomes irreversible. Electroneutral and anionic surfactants with long hydrocarbon chains may accumulate in a cellular membrane owing to the oxidative degradation of unsaturated radicals in lipid molecules. This finding may be used in the design of polymeric therapeutic means specifically interacting with damaged cells.     

Formation of a highly oxidized iron biliverdin complex upon treatment of a five-coordinate verdoheme with dioxygen

Treatment of a green solution of the five-coordinate octaethylverdoheme, XFeII(OEOP) 1 (X = Cl or Br), with dioxygen results in the formation of a new iron complex of octaethylbiliverdin, 2, within a matter of minutes. The reaction has been monitored by 1H NMR spectroscopy, and the product 2 (X = Cl) has been isolated and examined by X-ray crystallography. The structure of 2 (X = Cl) shows that the iron is five-coordinate with bonds to the four nitrogen atoms of the helical tetrapyrrole ligand and to an axial chloride. Treatment of 2 (X = Cl or Br) with zinc amalgam produces the known iron(III) complex of biliverdin, {FeIII(OEB)}2. The unusual pattern of resonances in the 1H NMR spectrum of 2 and its facile reduction to {FeIII(OEB)}2 indicate that 2 is an oxidized complex that can be formulated by resonance structures involving either an Fe(IV) ion bound to a bilindione trianion or an Fe(III) ion bound to an oxidized, dianionic, radical form of the ligand.     

AutoShim: empirically corrected scoring functions for quantitative docking with a crystal structure and IC50 training data

It has been notoriously difficult to develop general all-purpose scoring functions for high-throughput docking that correlate with measured binding affinity. As a practical alternative, AutoShim uses the program Magnet to add point-pharmacophore like "shims" to the binding site of each protein target. The pharmacophore shims are weighted by partial least-squares (PLS) regression, adjusting the all-purpose scoring function to reproduce IC 50 data, much as the shims in an NMR magnet are weighted to optimize the field for a better spectrum. This dramatically improves the affinity predictions on 25% of the compounds held out at random. An iterative procedure chooses the best pose during the process of shim parametrization. This method reproducibly converges to a consistent solution, regardless of starting pose, in just 2-4 iterations, so these robust models do not overtrain. Sets of complex multifeature shims, generated by a recursive partitioning method, give the best activity predictions, but these are difficult to interpret when designing new compounds. Sets of simpler single-point pharmacophores still predict affinity reasonably well and clearly indicate the molecular interactions producing effective binding. The pharmacophore requirements are very reproducible, irrespective of the compound sets used for parametrization, lending confidence to the predictions and interpretations. The automated procedure does require a training set of experimental compounds but otherwise adds little extra time over conventional docking.     

Isolation and structure of providencin: a highly oxygenated diterpene possessing a unique bicyclo[12.2.0]hexadecane ring system from the sea plume Pseudopterogorgia kallos

[structure: see text] Providencin (1) is a naturally occurring cytotoxin isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos. Its highly oxygenated hexacyclic structure is based on a previously undescribed bicyclo[12.2.0]hexadecane ring system and was established through spectroscopic analysis and X-ray crystallographic analysis. Providencin (1) was shown to exhibit modest anticancer activity against human breast (MCF7), lung (NCI-H460), and CNS (SF-268) cancer cell lines.     

A novel and highly efficient two-carbon ring expansion

[reaction: see text]. Dynamic gas-phase thermoisomerization (DGPTI) of medium- and large-ring 3-vinylcycloalkanones at 600-630 degrees C produces isomeric gamma,delta-unsaturated cycloalkanones expanded by two carbon atoms. A reaction mechanism involving an open-chain diradical intermediate, followed by intramolecular recombination under insertion of the vinyl group is proposed. Substituents on the vinyl moiety are transferred locospecifically to the ring-expanded ketones as corresponding beta- and gamma-substituents, respectively. The preparation of extraordinary cyclic allenes can be accomplished by DGPTI (540 degrees C) of 3-ethinylcyclododecanone.     

Sr(II) in water: A labile hydrate with a highly mobile structure

Despite the large number of experimental as well as theoretical investigations available in the literature, some properties of the hydration structure of Sr(II), for example, the coordination number, are still ambiguous. The presented molecular dynamics study based on a most suitable ab initio QM/MM protocol allowed a detailed investigation of structural and dynamical properties of this hydrate, which shows a considerable degree of internal flexebility as well as ligand mobility within the first shell. Despite the high computational effort an exceptionally long QM/MM simulation had to be carried out to obtain sufficient information to investigate first shell ligand exchange reactions.     

Studies on highly oxidized cyclohexanes. Constitution of a new key metabolic intermediate.

The absolute stereostructure of (?)1,6 desoxypipoxide ($\text{2}$), a new plant metabolite of biosynthetic significance was assigned by spectral interpretation and chemical correlation with (+)pipoxide ($\text{1}$).     

Trichilin B, a novel limonoid with highly rearranged ring system from Trichilia connaroides

Trichilin B (2), a limonoid having an unprecedented highly rearranged ring system, along with biosynthetically correlated trichilin A (1), was isolated from Trichilia connaroides. The structures were elucidated by spectroscopic analysis. Compound 2 features a unique 9,17-oxygen bridge, while two unprecedented δ-lactone rings fused to rings A and B at C-5, C-9 and ring C at C-8, C-14. Their cytotoxic activities were also evaluated.