Global 3D-QSAR methods: MS-WHIM and autocorrelation.
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.
Gancia
E
E
Italfarmaco Research Centre, Milan, Italy. emanuelagancia@chiroscience.com
Bravi
G
G
Mascagni
P
P
Zaliani
A
A
D016232:Endothelins / Q000037:antagonists & inhibitors; D054303:HIV Reverse Transcriptase / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
D016232:Endothelins; D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides; D054303:HIV Reverse Transcriptase