GalaxyDock2: Protein–ligand docking using beta‐complex and global optimization

In this article, an enhanced version of GalaxyDock protein–ligand docking program is introduced. GalaxyDock performs conformational space annealing (CSA) global optimization to find the optimal binding pose of a ligand both in the rigid‐receptor mode and the flexible‐receptor mode. Binding pose prediction has been improved compared to the earlier version by the efficient generation of high‐quality initial conformations for CSA using a predocking method based on a beta‐complex derived from the Voronoi diagram of receptor atoms. Binding affinity prediction has also been enhanced by using the optimal combination of energy components, while taking into consideration the energy of the unbound ligand state. The new version has been tested in terms of binding mode prediction, binding affinity prediction, and virtual screening on several benchmark sets, showing improved performance over the previous version and AutoDock, on which the GalaxyDock energy function is based. GalaxyDock2 also performs better than or comparable to other state‐of‐the‐art docking programs. GalaxyDock2 is freely available at http://galaxy.seoklab.org/softwares/galaxydock.html . © 2013 Wiley Periodicals, Inc.     

An efficient and solvent-free one-pot multi-component synthesis of novel highly substituted pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives catalyzed by tetramethylguanidine

Abstract

An efficient solvent-free access towards highly substituted pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives has been established through multi-component reaction of 1H‐pyrazolo[3,4‐b]pyridin‐3‐amine, aldehyde, 3-(1H-indol-3-yl)-3-oxopropanenitrile catalyzed by 1,1,3,3-tetramethylguanidine (TMG). The reaction allows the formation of one C?C and two C?N bonds with high yield. The significant features of this solvent-free reaction include mild reaction condition, readily accessible substrates, short reaction time, excellent yield, and broad substrate scopes as well as simple one-pot operation, no column chromatographic purification, which makes this strategy highly attractive.     

Catalytic Enantioselective Quick Route to Aldol‐Tethered 1,6‐ and 1,7‐Enynes from ω‐Unsaturated Aldehydes

An effective asymmetric route to functionalized 1,6‐ and 1,7‐enynes has been developed based on a direct cross‐aldol reaction between ω‐unsaturated aldehydes and propargylic aldehydes (α,β‐ynals) promoted by combined α,α‐dialkylprolinol ether/Brønsted acid catalysis. This synergistic activation strategy is key to accessing the corresponding aldol adducts with high stereoselectivity, both enantio‐ and diastereoselectivity. The aldol reaction also proceeds well with propargylic ketones (α,β‐ynones) thus enabling a stereocontrolled access to the corresponding tertiary alcohols. The utility of these adducts, which are difficult to prepare through standard methodology, is demonstrated by their transformation into trisubstituted bicyclic enones using standard Pauson–Khand conditions.     

Prediction on the Origin of Selectivities in Base‐controlled Switchable NHC‐catalyzed Transformations

The base‐controlled mechanisms for N‐heterocyclic carbene (NHC)‐catalyzed divergent [3+3] and [3+2] annulation reactions were examined by using the DFT method. The reaction initiates with the complexation of NHC and enal to give the Breslow intermediate, which diverges afterward. Then, the azomethine imine can either react with the Breslow intermediate to give the six‐membered ring product or the β‐carbon protonation occurs for forming the enolate intermediate controlled by different bases. The formed enolate intermediate reacts with azomethine imine to afford the five‐membered ring product. The calculated results show that only the base K₂CO₃ can facilitate the structural transformation between homoenolate and enolate to switch the chemoselectivity; therefore, the [3+3] annulation happens preferentially in the presence of base DBU while the other situation occurs with K₂CO₃ as base. The NCI analysis results reveal that the stereoselectivity is predominately determined by the π???π, C?H???O, and C?H???N interactions. The obtained mechanistic insights should provide valuable clues for the rational design of these kinds of divergent reactions.     

Amino-substitutedgem-diphosphonic acids: Dissociation mechanism and the structure of species in aqueous solutions

The mechanism of dissociation of amino-substitutedgem-diphosphonic acids R₂N(CH₂) _n CR'(PO₃H₂)₂ with different lengths of the alkylidene chain and different substituents at the N atom was studied by vibrational (IR, Raman) and NMR (¹H,¹⁴N,³¹P) spectroscopy using data of conformational analysis (molecular mechanical) data. The important role of intramolecular H-bonds and cyclic solvates for the stabilization of various conformations and tautomeric forms of ions was demonstrated. The spectral data that allow one to consider thegem-diphosphonate group as a single acidic center were found. Translated fromIzvestiya Akademii Nauk Seriya Khimicheskaya, No. 6, pp. 1051–1064, June, 2000.     

Molecular mechanics-based conformational analysis of previtamin D and its A-ring analogues

Summary The ground-state conformational analysis of previtamin D and analogues with different substituents at C-3, C-1, and C-10 have been performed by force-field calculations. Differences in the photochemistry of these analogues are discussed in view of the concept of ground-state conformational control in photochemical reactions. The effect of complexes of previtamin D with silanol derivatives, formedvia hydrogen bonds, on their conformational equilibrium has been calculated. An increase in the population ofcZc conformers with increasing size of the silanol molecules (as a model for a heterogeneous silica surface) was observed.

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Konformationsanalyse von Previtamin D und seiner A-Ring-Analogen mit Hilfe von Kraftfeldrechnungen

Zusammenfassung Eine Konformationsanalyse des Grundzustandes von Previtamin D and von an C-1, C-3 und C-10 substituierten Analogen wurde mit Hilfe von Kraftfeldrechnungen durchgeführt. Unterschiedliches Reaktionsverhalten bei den photochemischen Umsetzungen dieser Verbindungen werden unter dem Gesichtspunkt der Grundzustandskontrolle von photochemischen Reaktionen diskutiert. Der Einfluß von Komplexbildung über Wasserstoffbrücken von Previtamin D mit Silanolen wurde berechnet. Eine Zunahme der Population dercZc-Konformeren mit zunehmender Größe des Silanols (ein Modell für eine heterogene Kieselgeloberfläche) wurde dabei beobachtet.

     

Structure Relaxation of n-alkanes Observed by the Simultaneous DSC-FTIR Method

Phase transitions of hexatriacontane (C36) and octacosane (C28), both as the solution grown single crystal (SGC) and polycrystalline aggregates (MCC) prepared by cooling at 1 K min^–1 from the isotropic liquid state, were measured by the simultaneous DSC-FTIR method. MCC of C36 showed the freezing of the high temperature stable phase, which had a slight lower order of the lattice vibration mode comparing with the room temperature stable phase. MCC of C28 demonstrated thermo-reversible phase transition, however, had a binomial distribution of crystal stability of the monoclinic phase.This revised version was published online in November 2005 with corrections to the Cover Date.