A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists

Summary In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first generate and optimize all low-energy conformations by any suitable method. For each conformation we then use ALAD-DIN to calculate the location of points to be considered as part of the superposition. These points include atoms in the molecule and projections from the molecule to hydrogen-bond donors and acceptors or charged groups in the binding site. These positions and the relative energy of each conformation are the input to our new program DISCO. It uses a clique-detection method to find superpositions that contain a least one conformation of each molecule and user-specified numbers of point types and chirality. DISCO is fast; for example, it takes about 1 min CPU to propose pharmacophores from 21 conformations of seven molecules. We typically run DISCO several times to compare alternative pharmacophore maps. For D₂ dopamine agonists DISCO shows that the newer 2-aminothiazoles fit the traditional pharmacophore. Using site points correctly identifies the bioactive enantiomers of indoles to compare with catechols whereas using only ligand points leads to selecting the inactive enantiomer for the pharmacophore map. In addition, DISCO reproduces pharmacophore maps of benzodiazepines in the literature and proposes subtle improvements. Our experience suggests that clique-detection methods will find many applications in computational chemistry and computer-assisted molecular design.     

The interaction of aromatic hydrocarbons with organometallic compounds of the main group elements. : IV. The preparation and structure of the novel selenide K[CH3Se{Al(CH3)3}3] · 2C6H6

The crystal structure of K[CH₃Se {Al(CH₃)₃}₃] · 2C₆H₆ has been determined from single-crystal X-ray diffraction data collected by counter methods. The compound crystallizes in the triclinic space group P$\text{1}$ with cell dimensions a = 17.165(7), b = 10.144(7), c = 10.156(7)Å, α = 119.26(5), β = 104.07(5), ψ = 80.51(5)°, and Dc = 1.12 gcm^?3 for Z = 2. Least-squares refinement gave a final R value of 0.083 for 1967 independent observed reflections. One of the two benzene molecules in the asymmetric unit has been located by difference Fourier techniques. Because of either extreme disorder or high thermal motion, the aromatics make practically no contribution to the X-ray scattering. The selenium atom in the anion exhibits tetrahedral coordination. The Al-Se bond lengths average 2.578(5)Å, and the Se-C distance is 1.93(2)Å.     

On the partitioning of energy for Atoms,Ions, and Molecules

The fact that, for neutral atoms, the interelectronic repulsion energy I is a constant fraction (1/3) of the total energy E is discussed in the light of several approximate energy formulas, theoretical and empirical. We then derive the asymptotic form of the non-relativistic energy of a neutral atom as E=–kZ ^7/3 a.u. (Z = atomic number) with k probably between 1/2(3/2)^1/3 and 9/14(3/2)^1/3. For 6Z90, the actual energies are in fact between these limits, while the formula implies I/E=1/3. The ratio of interelectronic repulsion energy to total electronic energy for ions and molecules is derived.

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Zusammenfassung Mit der Hilfe einiger theoretischer und empirischer Näherungsformeln wird die Tatsache diskutiert, daß für neutrale Atome die zwischenelektronische Abstoßungsenergie I stets etwa 1/3 der elektronischen Gesamtenergie E beträgt. Die asymptotische Form der nicht relativistischen Energie eines neutralen Atoms wird dann zu E=–kZ^1/3 abgeleitet, wobei Z die Kernladungszahl st und k wahr 1/2(3/2)^1/3 und 9/14(3/2)1/3 scheinlich zwischen 1/2 und 9/14(3/2)^1/3 liegt. Für 6Z90 liegen die berechneten Energien tatsächlich innerhalb dieser Grenzen. Gleichzeitig enthält diese Formel das Verhältnis I/E=1/3. Ferner wird das Verhältnis von I zu E für Ionen und Moleküle abgeleitet.

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Résumé Nous discutons le fait que, pour les atomes neutres, l'énergie de répulsion interélectronique I est toujours à peu près 1/3 de l'énergie électronique totale E. Après avoir examiné le rapport entre ce fait et certaines formules théoriques et empiriques pour l'énergie, nous démontrons que la forme asymptotique de l'énergie est E=–kZ ^7/3 u.a. (Z = charge du noyau), avec k probablement entre 1/2(3/2)^1/3 et 9/14(3/2)^1/3. Les énergies calculées pour 6Z90 sont en accord avec cette règle. La formule E=–kZ ^7/3conduit aussi à I/E= 1/3. Nous démontrons également le rapport entre I et E pour les ions et les molecules.