Almond program

GRID and VolSurf are free programs available from the Internet at the site http //moldiscovery.com. The Almond program is a available from the Internet at www.moldiscovery.com. 

D-molecular descriptors, alignment-independent and based on molecular interaction, called GRIND have been developed. These are autocorrelation transforms that are independent of the orientation of the molecules in 3D space. The original descriptors can be extracted from the autocorrelation transform with the ALMOND program. The basic idea is to compress the information present in 3D maps into a few 2D numerical descriptors which are very simple to understand and interpret. 

Recently, pharmacophores have been defined from homology models of CYP isoforms in the ALMOND program (Pastor et al., 2000). This method is based on an assessment of complementarity between binding properties of substrates and the enzymic binding sites. It assumes that within the enzyme-substrate complex, the site of reaction in the enzyme (the reactive oxygen atom) coincides... 

The PLS multivariate data analysis of the training set was carried out on the descriptors matrix to correlate the complete set of variables with the activity data. From a total of 710 variables, 559 active variables remained after filtering descriptors with no variability by the ALMOND program. The PLS analysis resulted in four latent variables (LVs) with / = 0.76. The cross validation of the model using the leave-one-out (LOO) method yielded values of 0.72. As shown in Table 9.2, the GRIND descriptors 11-36, 44-49, 12-28, 13-42, 14-46, 24-46 and 34-45 were found to correlate with the inhibition activity in terms of high coefficients. 

PLS analysis was performed on the reduced set to identify a correlation between the complete set of variables and the activity data. The ALMOND program kept 624 active variables out of a total of 750 variables after filtering out descriptors with no variability. The 45 compounds with two basic nitrogen atoms were proton-ated on just one of the two basic centers. For these compounds, two models were built using one of the two isomers at a time. The isomer that produced the model with the best r was chosen. The PLS analysis resulted in a model with three LVs and r = 0.77. The cross validation of the model by the LOO method yielded q values of 0.74. As shown in Table 9.2, the GRIND descriptors that had high coefficients in the PLS model were 11-36, 44-58, 12-41, 13-40, 14-47, 24-52, and 34-49. 

To avoid the issue of alignments in 3D-QSAR, several autocorrelation methods have been proposed by the groups of Broto et al. [101], Wagener et al. [102], and Clementi et al. [103]. Except for Broto et al. s method (used on 2-D or 3-D structures), these methods require a 3-D molecular structure, i.e., they are based on the choice of a conformer. The ALMOND program [25], built on initial work from Clementi et al. [103], is described below because of its convenient use of graphical outputs that relate autocorrelation vectors to MIFs, as well as to molecular structures. 

A) Separation of fatty acid methyl esters derived from almond oil on a BPX-5 column (12 m X 0.25 mm i.d. x 0.25 pm film). Programmed 100° (1 min) then 107min to 320°. The major peaks are shown as offscale so that the minor peaks can be seen clearly. (B) The same sample separated on a HP Stabiliwax column (15 m X 0.25 mm x 0.5 pm film). Programmed 140°... 

Einally, there is a fourth program which encapsulates GRIND descriptors named ALMOND. ALMOND theory is described in Chapter 6. What we will describe below refers to our involvement in utilizing the GRIND descriptors to model and understand various ADME and safety properties. 

All QSAR analysis was carried out using the program ALMOND 3.2.0 and grid alignment independent descriptors (GRIND). 

VolSurfwas initially validated on oral absorption [16, 17] and blood-brain-barrier permeation [18] models (see belovi ). VolSurf has continued to be developed to improve in silico predictions for ADME properties, although its use has also been extended to receptor-based evaluation of binding affinity [19, 20], While other soft-ivare tools for ADME modeling are available (see, e.g., [21]), the MIF-based collection of sofhvare and models available from Molecular Discovery (MD) is both extensive and ivell validated by the private sector. Three programs from MD, VolSurf, MetaSite and Almond, are particularly suited for rapid evaluation of large compound sets [22] in connection ivith ADME/Tox related properties ... 

The GRID force field represents the basis for several software packages specifically developed for application to pharmacodynamic aspects of drug research, including the programs ALMOND, Pathfinder, and FLAP or, in the ADME field, the programs VolSurf and MetaSite. 

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