RESUMEN
Hydrogen bonding interactions play a major role in many chemical and biological processes. This article describes the development of a method for the quantitative estimation of the hydrogen-bonding donor strengths of OH/NH moieties and of the hydrogen bonding acceptor strengths of O/N atoms in different chemical structures. The method is based on the correlation of experimentally observed hydrogen-bonding strengths with quantum-mechanical derived properties, calculated on the acceptor atom (for hydrogen-bond acceptors) and on the heavy atom attached to the donor hydrogen (for hydrogen-bond donors). The properties giving the best correlation with the experimental hydrogen bonding scales were electrophilic superdelocalizability and self-atom polarizability. The best equations found have been implemented in a Web-based tool for hydrogen-bond strength prediction.
Asunto(s)
Diseño de Fármacos , Enlace de Hidrógeno , Programas Informáticos , Gráficos por Computador , Simulación por Computador , Bases de Datos como Asunto , Modelos Químicos , Protones , Teoría CuánticaRESUMEN
The recently proposed MS-WHIM indices, a set of theoretical descriptors containing information about size, shape and electrostatic distribution of a molecule, have been further investigated. The main objectives of this work were: (i) to confirm the descriptive power of MS-WHIM in modelling specific biological interactions, (ii) to analyse the dependence of MS-WHIM on the type of atomic charges used for computing electrostatic potential and (iii) to compare the performances of MS-WHIM with those provided by other global 3D molecular descriptors. The spatial autocorrelation of atomic and molecular surface properties were selected for comparison purposes. WHIM-based and autocorrelation-based vectors were calculated for two molecular sets from the literature, namely a series of 18 HIV-1 reverse transcriptase inhibitors and a set of 36 sulphonamide endothelin inhibitors. PLS was adopted to derive statistical predictive models that were validated by means of cross-validation. The reported results confirmed that MS-WHIM indices are able to provide meaningful statistical correlations with biological activity. MS-WHIM descriptors are sensitive to the type of partial atomic charges applied and improved models were obtained using more accurate charges. Moreover for both the datasets, MS-WHIM results, in terms of fitting and predictive power of PLS models, were superior to those from autocorrelation. Finally, the strengths/weaknesses of global 3D-QSAR descriptors over local CoMFA-like methods, as well as the main differences between WHIM-based and autocorrelation-based vectors, are discussed.
Asunto(s)
Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Sulfonamidas/farmacología , Endotelinas/antagonistas & inhibidores , Transcriptasa Inversa del VIH/efectos de los fármacos , Electricidad Estática , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
The recently proposed WHIM (Weighted Holistic Invariant Molecular) approach [Todeschini, R., Lasagni, M. and Marengo, E., J. Chemometrics, 8 (1994) 263] has been applied to molecular surfaces to derive new 3D theoretical descriptors, called MS-WHIM. To test their reliability, a 3D QSAR study has been performed on a series of steroids, comparing the MS-WHIM description to both the original WHIM indices and CoMFA fields. The analysis of the statistical models obtained shows that MS-WHIM descriptors provide meaningful quantitative structure-activity correlations. Thus, the results obtained agree well with those achieved using CoMFA fields. The concise number of indices, the ease of their calculation and their invariance to the coordinate system make MS-WHIM an attractive tool for 3D QSAR studies.