Global 3D-QSAR methods: MS-WHIM and autocorrelation

The recently proposed MS-WHIM indices, a set of theoretical descriptors con taining information about size, shape and electrostatic distribution of a m olecule, have been further investigated. The main objectives of this work w ere: (i) to confirm the descriptive power of MS-WHIM in modelling specific biological interactions, (ii) to analyse the dependence of MS-WHIM on the t ype 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 molecul ar 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 inhibitor s and a set of 36 sulphonamide endothelin inhibitors. PLS was adopted to de rive statistical predictive models that were validated by means of cross-va lidation. The reported results confirmed that MS-WHIM indices are able to p rovide meaningful statistical correlations with biological activity. MS-WHI M descriptors are sensitive to the type of partial atomic charges applied a nd improved models were obtained using more accurate charges. Moreover for both the datasets, MS-WHIM results, in terms of fitting and predictive powe r of PLS models, were superior to those from autocorrelation. Finally, the strengths/weaknesses of global 3D-QSAR descriptors over local CoMFA-like me thods, as well as the main differences between WHIM-based and autocorrelati on-based vectors, are discussed.