Unsupervised guided docking of covalently bound ligands

Summary An approach for docking covalently bound ligands in protein enzymes or receptors was implemented in MacDOCK, a similarity-driven docking program based on DOCK 4.0. This approach was tested with a small number of covalent ligand–protein structures, using both native and non-native protein structures. In all cases, MacDOCK was able to generate orientations consistent with the known covalent binding mode of these complexes, with a performance similar to that of other docking programs. This method was also applied to search for known covalent thrombin inhibitors in a medium-sized molecular database (ca. 11,000 compounds). Detection of functional groups suitable for covalent docking was carried out automatically. A significant enrichment in known active molecules in the first 5% of the database was obtained, showing that MacDOCK can be used efficiently for the virtual screening of covalently bound ligands.     

Diphenoxyethyne: A highly electrophilic acetylene diether

Diphenoxyethyne, the first diaryloxyacetylene so far described in the chemical literature, has been synthesized from 1,2-diphenoxyethane in a five-step sequence; the compound is a highly electrophilic species that adds even poor nucleophiles, such as $\text{tert}$-butoxide and bis-(trimethylsilyl)amide.     

Electro-organic reactions : Part 34. Kinetic basicities of some electrogenerated organic dianions and the competition between protonation and reproportionation

Convenient and reliable double potential step chronamperometry methods are described for measurement of the rates of protonation of 9-fluorenylidene dianions by carbon acids. The rates of protonation are shown to be insensitive to competing base-catalysed enolisation of the carbon acid. Comparison of experimental i-t transients with those simulated for plausible mechanisms shows that although the measured protonation rate constants are affected by allowing for rapid reproportionation, they are all affected in a similar manner. In contrast, ion-pairing or complexation effects are significant; protonation rate differences caused by varying cation: dianion interactions have been measured and explained. For the dianion of diethyl(4,5-diazafluoren-9-ylidene)malonate a 1:2 complex is formed with Na⁺ and its formation constant in DMSO has been measured as 1.7 × 10⁸.     

The calculation of electron localization and delocalization indices at the Hartree–Fock, density functional and post-Hartree–Fock levels of theory

 Localization, λ(A), and delocalization indices, δ(A,B), as defined in the atoms in molecules theory, are a convenient tool for the analysis of molecular electronic structure from an electron-pair perspective. These indices can be calculated at any level of theory, provided that first- and second-order electron densities are available. In particular, calculations at the Hartree–Fock (HF) and configuration interaction (CI) levels have been previously reported for many molecules. However, λ(A) and δ(A,B) cannot be calculated exactly in the framework of Kohn–Sham (KS) density functional theory (DFT), where the electron-pair density is not defined. As a practical workaround, one can derive a HF-like electron-pair density from the KS orbitals and calculate approximate localization and delocalization indices at the DFT level. Recently, several calculations using this approach have been reported. Here we present HF, CI and approximate DFT calculations of λ(A) and δ(A,B) values for a number of molecules. Furthermore, we also perform approximate CI calculations using the HF formalism to obtain the electron-pair density. In general, the approximate DFT and CI results are closer to the HF results than to the CI ones. Indeed, the approximate calculations take into account Coulomb electron correlation effects on the first-order electron density but not on the electron-pair density. In summary, approximate DFT and CI localization and delocalization indices are easy to calculate and can be useful in the analysis of molecular electronic structure; however, one should take into account that this approximation increases systematically the delocalization between covalently bonded atoms, with respect to the exact CI results. Received: 13 February 2002 / Accepted: 24 April 2002 / Published online: 18 June 2002     

Synthesis, structure, and substitution mechanism of new Ru(II) complexes containing 1,4,7-trithiacyclononane and 1,10-phenanthroline ligands

Two new Ru complexes containing the 1,10-phenanthroline (phen) and 1,4,7-trithiacyclononane ([9]aneS3, SCH2CH2SCH2CH2SCH2CH2) ligands of general formula [Ru(phen)(L)([9]aneS3)]2+ (L = MeCN, 3; L = pyridine (py), 4) have been prepared and thoroughly characterized. Structural characterization in the solid state has been performed by means of X-ray diffraction analyses, which show a distorted octahedral environment for a diamagnetic d6 Ru(II), as expected. 1H NMR spectroscopy provides evidence that the same structural arrangement is maintained in solution. Further spectroscopic characterization has been carried out by UV-vis spectroscopy where the higher acceptor capability of MeCN versus the py ligand is manifested in a 9-15-nm blue shift in its MLCT bands. The E1/2 redox potential of the Ru(III)/Ru(II) couple for 3 is anodically shifted with respect to its Ru-py analogue, 4, by 60 mV, which is also in agreement with a higher electron-withdrawing capacity of the former. The mechanism for the reaction Ru-py + MeCN--> Ru-MeCN + py has also been investigated at different temperatures with and without irradiation. In the absence of irradiation at 326 K, the thermal process gives kinetic constants of k2 = 1.4 x 10(-5) s(-1) (DeltaH(++) = 108 +/- 3 kJ mol(-1), DeltaS(++) = -8 +/- 9 J K(-1) mol(-1)) and k-2 = 2.9 x 10(-6) s(-1) (DeltaH(++) = 121 +/- 1 kJ mol(-1), DeltaS(++) = 18 +/- 3 J K(-1) mol(-1)). The phototriggered process is faster and consists of preequilibrium formation of an intermediate that thermally decays to the final Ru-MeCN complex with an apparent rate constant of (k1Khnu)app = 1.8 x 10(-4) s(-1) at 304 K, under the continuous irradiation experimental conditions used.     

Organometallic compounds of transition metals containing phosphine and perchloroaryl ligands I. Preparation and studies of compounds of the type [MX(C6Cl5)(PPh3)2] (M  Ni,Pd)

Several stable new compounds of transition metals with C₆Cl₅ as ligand, of the type [MX(C₆Cl₅)(PPh₃)₂] (M  Pd and X  Cl, Br, I, NCS, NCO, N₃; M  Ni and X  NCS, NCO, N₃) are described. Their preparation in some cases required in situ reaction of [MX₂(PPh₃)₂], Mg and C₆Cl₆. The action of gaseous HCl and Cl₂ on the solutions of these compounds has been examined. The IR spectra of the cyanato and thiocyanato complexes indicates coordination through the nitrogen atom.     

On the calculation of ab initio quantum molecular similarities for large systems: Fitting the electron density

A set of procedures for rapid calculation of quantum molecular similarities from ab initio wave functions is discussed. In all cases a density fitting is carried out to eliminate the need of calculating costly four-centered integrals. It is proved that this methodology can be applied to large systems to reproduce exact quantum molecular similarity measures at an extremely low computational cost. © 1994 by John Wiley & Sons, Inc.     

A General Analysis of Field-Based Molecular Similarity Indices

A formalism is presented that incorporates the entirety of all field-based molecular similarity indices of general form S _ij = _ij /h( _ii , _jj ), where the numerator is given by the inner product or overlap of field functions F _i and F _j corresponding to the ith and jth molecules, respectively, and the denominator is given by a suitable mean function of the self-similarities _ii and _jj . This family of similarity indices includes the index initially introduced by Carbó nearly twenty years ago, where h( _ii , _jj ) is taken to be the geometric mean of _ii and _jj , and the well-known indices due to Hodgkin and Richards, and Petke, where h( _ii , _jj ) is taken to be the arithmetic mean and maximum of _ii and _jj , respectively. Two new indices based upon the harmonic mean and minimum of _ii and _jj are also defined, and it is demonstrated that the entire set of field-based similarity indices can be generated from a one-parameter family of functions, called generalized means, through proper choice of the parameter value and suitable limiting procedures. Ordering and rigorous bounds for all of the indices are described as well as a number of inter-relationships among the indices. The generalization of field-based similarity indices, coupled with the relationships among indices that have been developed in the present work, place the basic theory of these indices on a more unified and mathematically rigorous footing that provides a foundation for a better understanding of the quantitative aspects of field-based molecular similarity.