WHIM descriptors

D MoRSE desaiptor, radial distribution function (RDF code), WHIM descriptors, GETAWAY descriptors,... 

WHIM descriptors Weighted Holistic Invariant Molecular descriptors) are discussed in detail in the Handbook, Chapter XIII, Section 2 [48, 49]. 

Bravi G, Wikel JH. Application of MS-WHIM descriptors 1. Introduction of new molecular surface properties and 2. Prediction of binding affinity data. 

Ekins et al. (163) used the rat ortholog 2B6 to generate a pharmacophore model and compared these findings with a partial least squares (PLS) model using MS-WHIM descriptors. The model was constructed using 16 B-lymphoblastoids and yielded a good cross-validated r2 of 0.607. The analysis included molecular surface properties (size) together with positive elec-... 

Ekins et al. (201) used the MS-WHIM descriptors to construct 3D and 4D QSAR models for the log(l/Aj) of 14 competitive inhibitors of CYP3A. The 3D QSAR of the CYP3A4-mediated midazolam l -hydroxylation was shown to be predictive yielding a leave-one-out (LOO) q2 value of 0.32. Although the 4D QSAR methodology includes conformational changes, it did not provide for a significant improvement over the 3D QSAR (LOO q2 0.44). Two other datasets (242,243) were used to create 3D and 4D QSAR models. In both datasets, it was not possible to build predictive 3D QSAR models however, 4D QSAR models were constructed (LOO q2 = 0.41-0.56). 

Todeschini, R. and Gramatica, P., 3D-modelling and prediction by WHIM descriptors. Part 5. Theory development and chemical meaning of WHIM descriptors, Quant. Struct.-Act. Relat., 16, 113-119, 1997b. 

Examples of such descriptors are - WHIM descriptors and -> G-WHIM descriptors of size and shape, -> EA indices, - quasi-Wiener index, - Mohar indices, several - shape descriptors, - EVA descriptors and EEVA descriptors. 

The electrotopological states are local vertex invariants. After rescaling, they are also used as atomic weighting factors for the calculation of the -> WHIM descriptors. 

Examples of geometrical descriptors are the - quantum-chemical descriptors, -> moment of inertia, - length-to-breadth ratio, -> surface areas, - volume descriptors, - CPSA descriptors, -> EVA descriptors, -> WHIM descriptors, 3D-MoRSE descriptors, -> interaction energy values, spectrum-like descriptors. 

The most popular grid-based QSAR techniques are - GRID method and -> CoMFA a number of related techniques has also been proposed such as - CoMSIA, - Voronoi Molecular Field Analysis, -> hydration free energy density, and the approach based on - G-WHIM descriptors. 

Grid-Weighted Holistic Invariant Molecular descriptors G-WHIM descriptors... 

Based on a similar approach to that used to define - WHIM descriptors, G-WHIM descriptors [Todeschini et al, 1997a Todeschini and Gramatica, 1998] are global molecular descriptors of - molecular interaction fields. 

Once the optimal choices for the grid have been made, the G-WHIM descriptors are used to condense the whole information contained in the scalar field constituted by the calculated - interaction energy values into a few global parameters, whose values are independent of the molecular orientation within the grid. 

For each molecule, the G-WHIM descriptors are calculated by the following steps ... 

This assumption leads to two sets of G-WHIM descriptors one describing the positive part of the molecular field, the other describing the negative part. 

Thus, for each region [positive (+) and negative (-)], the G-WHIM descriptors consist of 8 directional plus 5 non-directional molecular descriptors (26 for a complete description of each interaction field), calculated from each molecule ... 

The directional y and the non-directional G parameters, defined for WHIM descriptors and containing information about the molecular symmetry, are not considered in the frame of the G-WHIM approach as their meaning becomes doubtful, depending heavily upon the point sampling. However, information regarding molecular symmetry can be obtained by directly using the WHIM symmetry parameters. 

The meaning of the G-WHIM descriptors is that previously defined for WHIM descriptors, but now the descriptors refer to the interaction molecular field instead of the molecule. For example, the eigenvalues X,i, Xz and >,3, relate to the interaction field size the eigenvalue proportions i9i and i>2 relate to the interaction field shape the group of descriptors constituted by the inverse function of the kurtosis (k), i.e., = 1/k ... 

It must be noted that the invariance to rotation of G-WHIM descriptors, i.e. the independence of any molecular alignment rule, is obtained if the grid points are dense enough. In fact, a too sparse distribution of grid points represents an inadequate sampling of the ideal scalar field and is not able to guarantee that the calculated scalar field is representative of the ideal scalar field in such a way as to preserve rotational invariance. 

The G-WHIM approach integrates the information contained in WHIM descriptors and overcomes any problems due to the alignment of the different molecules and the explosion of variables arising from traditional - grid-based QSAR techniques. In particular, the G-WHIM approach can take into account either all the points within the cut-off values, excluding only positive interactions within the inner part of the molecule, or the surface points at a cut-off value, i.e. points on an iso-potential-energy surface. G-WHIM descriptors calculated on the -> Connolly surface area are also called MS-WHIM [Bravi et al, 1997]. 

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