Postprocessing of docked protein-ligand complexes using implicit solvation models

Molecular docking plays an important role in drug discovery as a tool for the structure-based design of small organic ligands for macromolecules. Possible applications of docking are identification of the bioactive conformation of a protein-ligand complex and the ranking of different ligands with respect to their strength of binding to a particular target. We have investigated the effect of implicit water on the postprocessing of binding poses generated by molecular docking using MM-PB/GB-SA (molecular mechanics Poisson-Boltzmann and generalized Born surface area) methodology. The investigation was divided into three parts: geometry optimization, pose selection, and estimation of the relative binding energies of docked protein-ligand complexes. Appropriate geometry optimization afforded more accurate binding poses for 20% of the complexes investigated. The time required for this step was greatly reduced by minimizing the energy of the binding site using GB solvation models rather than minimizing the entire complex using the PB model. By optimizing the geometries of docking poses using the GB(HCT+SA) model then calculating their free energies of binding using the PB implicit solvent model, binding poses similar to those observed in crystal structures were obtained. Rescoring of these poses according to their calculated binding energies resulted in improved correlations with experimental binding data. These correlations could be further improved by applying the postprocessing to several of the most highly ranked poses rather than focusing exclusively on the top-scored pose. The postprocessing protocol was successfully applied to the analysis of a set of Factor Xa inhibitors and a set of glycopeptide ligands for the class II major histocompatibility complex (MHC) A(q) protein. These results indicate that the protocol for the postprocessing of docked protein-ligand complexes developed in this paper may be generally useful for structure-based design in drug discovery.     

Determination of Nicotine in Dried Mushrooms by Using a Modified QuEChERS Approach and GC–MS–MS

Levels of nicotine higher than the maximum residue level were detected in edible mushrooms. Analyses of self-collected and purchased dried mushrooms were performed with a QuEChERS approach. A small amount (2.5 g) of dried sample matrix was mixed with 5 mL sodium hydroxide solution, 2.5 g of sodium sulfate/sodium chloride mixture (4:1) and 5 mL ethyl acetate. The organic phase was cleaned by using dispersive solid-phase extraction and analysed by GC–MS–MS. The linear range of the method was 0.01–10.00 mg kg^?1 and the limit of detection 0.006 mg kg^?1 on dry weight basis by using EURACHEM method.     

The Total Synthesis of (−)‐Nitidasin

Nitidasin is a pentacyclic sesterterpenoid with a rare 5‐8‐6‐5 carbon skeleton that was isolated from the Peruvian folk medicine “Hercampuri”. It belongs to a small class of sesterterpenoids that feature an isopropyl trans‐hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans‐hydrindanone, followed by chemoselective epoxidation, ring‐closing olefin metathesis, and redox adjustment.     

New In Situ Trapping Metalations of Functionalized Arenes and Heteroarenes with TMPLi in the Presence of ZnCl2 and Other Metal Salts

The addition of TMPLi to a mixture of an aromatic or heteroaromatic substrate with a metal salt such as MgCl₂, ZnCl₂, or CuCN at ?78 °C first leads to lithiation of the arene followed by transmetalation with the metal salt to afford functionalized organometallic compounds of Mg, Zn, or Cu. This in situ trapping method allows an expedited metalation (?78 °C, 5 min) of a range of sensitive pyridines (bearing a nitro, ester, or cyano group) and allows the preparation of kinetic regioisomers of functionalized aromatic compounds or heterocycles not otherwise available by standard metalating agents, such as TMPMgCl?LiCl or TMPZnCl?LiCl.     

Site‐Selective C−H Oxygenation via Aryl Sulfonium Salts

Herein, we report a two‐step process forming arene C?O bonds in excellent site‐selectivity at a late‐stage. The C?O bond formation is achieved by selective introduction of a thianthrenium group, which is then converted into C?O bonds using photoredox chemistry. Electron‐rich, ‐poor and ‐neutral arenes as well as complex drug‐like small molecules are successfully transformed into both phenols and various ethers. The sequence differs conceptually from all previous arene oxygenation reactions in that oxygen functionality can be incorporated into complex small molecules at a late stage site‐selectively, which has not been shown via aryl halides.     

New Light on an Old Story: The Crystal Structure of Boron Tetrathiophosphate Revisited

The crystal structure of boron tetrathiophosphate BPS₄ was reinvestigated using single‐crystal X‐ray diffraction. The structure shows unidimensional chains similar to SiS₂ as structural motifs. BPS₄ crystallizes in the orthorhombic space group Ibam (no. 72), with a = 5.6173(3), b = 8.9929(4), c = 5.2433(3) Å and V = 264.87(2) ų and is closely related to the orthorhombic high‐temperature modification of AlPS₄ (ht‐AlPS₄). The SiS₂‐like chains are all oriented parallel to the c axis, which explains the needle‐like morphology and that the crystals easily cleave to thinner needles under mechanical stress. While ht‐AlPS₄ shows an ordered Al‐P sublattice, the B‐P sublattice in BPS₄ is substantially disordered. The thermal properties of BPS₄ were investigated by DTA measurements and a detailed analysis of the Raman spectrum assisted by quantum mechanical calculations is presented. The crystallographic disorder in BPS₄ is the result of inter‐chain disorder, whereas local intra‐chain ordering of B and P can be concluded from Raman spectroscopy.     

Sustainable and highly controlled aryl couplings revealed by systematic assessment of photoactivatable linkers

The controlled synthesis of biphenyls, which play a prominent role in pharmaceuticals, agrochemicals, and liquid crystals, typically requires hazardous organometallic reagents, aryl halides, and heavy metal catalysts. We recently reported a metal-free, photochemical alternative (“photosplicing”) for the selective preparation of a wide range of pharmaceutically important biphenyls. Whereas the traceless sulfonamide linker enables and controls the aryl coupling, unwanted toxic byproducts are released. Therefore, we designed over 25 different temporary linkers and tested them for their suitability for the photosplicing reaction in a flow reactor. We found that a surprisingly high number of functional groups enable light-induced aryl fusion and identified a number of linkers for environmentally friendly procedures. We also report that a thiol-ene (click) – photosplicing sequence enables a convenient route to biaryls such as liquid crystals. This work sheds light on thus far neglected photochemistry of temporary linkers, reduces toxic byproducts, and expands the available starting materials for metal-free biphenyl synthesis.

A series of photoactivatable linkers for metal-free biphenyl synthesis is presented. Alternative substrates for the photosplicing reaction can reduce toxic byproducts and problematic starting materials.     

Quantum dynamics in the highly discrete, commensurate Frenkel Kontorova model: a path-integral molecular dynamics study

The commensurate Frenkel Kontorova (FK) model is studied using path-integral molecular dynamics (PIMD). We focus on the highly discrete case, in which the embedding potential has a much greater maximum curvature than the harmonic potential connecting two particles in the FK chain. When efficient sampling methods are used, the dynamical interpretation of adiabatic PIMD appears to represent quite accurately the true time correlation functions of this highly correlated many-body system. We have found that the discrete, quantum FK model shows different behavior than its continuum version. The spectral density does not show the characteristic omega-2Theta(omega-omegac) cusp of the continuum solution in the pinned phase (m>m(c)). We also identify a dynamical quantum hysteresis in addition to the regular classical hysteresis when an external force is applied to the FK chain. In the unpinned phase (m相似文献   

Towards protein folding with evolutionary techniques

We present design details and first tests of a new evolutionary algorithm approach to ab initio protein folding. It does not focus on dihedral angles exclusively, but mainly operates on introduction, extension, break-up, and destruction of secondary structure elements, given as correlated dihedral angle values. In first test applications to polyalanines (up to 60 residues) and random primary sequences (up to 40 residues), we demonstrate that this use of prior knowledge is well balanced: On the one hand, it ensures quick introduction of secondary structure elements if they are favorable for a given primary sequence, but still allows for efficient location of pure random coil solutions without enforcing any secondary structure elements, if folds of this type are preferred by the given primary sequence. Furthermore, the algorithm is clearly able to pack several secondary structure elements into favorable tertiary structure arrangements, although no part of the algorithm is explicitly designed to do this. In first test examples on real-life peptides between 21 and 44 residues from the Protein Data Bank, the quality of the results depends on the force field used (as expected); nevertheless, we can show that the algorithm is able to find structures in good agreement with the targets easily and consistently, if the force field allows for that.