Molecular interaction field -based method

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

A, B and V are constant for a given solute (Eig. 12.4 shows the value of A, 0.78, for atenolol). This means that the balance between intermolecular forces varies with the system investigated as would be expected from a careful reading of Section 12.1.1.3. This can also be demonstrated by using a completely different approach to factorize log P, i.e. a computational method based on molecular interaction fields [10]. Volsurf descriptors [11] have been used to calculate log P of neutral species both in n-octanol-water and in alkane-water [10]. 

We have presented a netv procedure, called PathFinder, aimed at encoding the GRID molecular interaction fields into invariant shape-descriptors, suitable for similarity and complementarity issues. Shape similarity is the underlying foundation of ligand-based methods tvhile shape complementarity is the basis of many receptor-based designs. 

Mannhold, R., Berellini, G., Carosati, E., Benedetti, P. Use of MIF-based VolSurf descriptors in physicochemical and pharmacokinetic studies. In Molecular Interaction Fields (Cruciani, G., Ed.), In Methods and Principles in Medicinal Chemistry (Mannhold, R., Kubinyi, H., Folkers, G., Eds), Vol. 27, Wiley-VCH Weinheim, 2006, pp. 173-196. 

The most popular grid-based QSAR techniques are GRID and CoMPA, based on molecular interaction fields derived from different probes these methods together with a number of related techniques are discussed below other related techniques are —> hydration free energy density and —> Comparative Molecular Surface Aitalysis. 

Still based on molecular interaction fields, several other methods were successively proposed and, among them, there were Comparative Molecular Similarity Indices Analysis (CoMSIA) ]Klebe, Abraham et al, 1994], Compass method ]Jain, Koile et al, 1994], G-WHIM descriptors ]Todeschini, Moro et al, 1997], Voronoi field analysis [Chuman, Karasawa et al, 1998], VolSurf descriptors ]Crudani, Pastor et al, 2000], and GRIND descriptors ]Pastor, Cruciani et al, 2000]. 

Molecular interaction fields can also be generated using GRIN/GRID. This method is especially reliable because it is based on a very careful parametrization of the interaction terms. The parameters are founded from experimental crystallographic data that is, the direction, type and typical strength of a particular interaction are classified according to actual crystals. 

Besides the aforementioned descriptors, grid-based methods are frequently used in the field of QSAR quantitative structure-activity relationships) [50]. A molecule is placed in a box and for an orthogonal grid of points the interaction energy values between this molecule and another small molecule, such as water, are calculated. The grid map thus obtained characterizes the molecular shape, charge distribution, and hydrophobicity. 

Nearly all liquid simulations have been done using molecular mechanics force fields to describe the interactions between molecules. A few rare simulations have been completed with orbital-based methods. It is expected that it will still be a long time before orbital-based simulations represent a majority of the studies done due to the incredibly large amount of computational resources necessary for these methods. 

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