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An alternative approach is reported to compute property fields based on similarity
indices of drug molecules that have been brought into a common alignment. The fields
of different physicochemical properties use a Gaussian-type distance dependence, and
no singularities occur at the atomic positions. Accordingly, no arbitrary definitions
of cutoff limits and deficiencies due to different slopes of the fields are encountered.
The fields are evaluated by a PLS analysis similar to the CoMFA formalism. Two data
sets of steroids binding to the corticosteroid-binding-globulin and thermolysin inhibitors
were analyzed in terms of the conventional CoMFA method (Lennard-Jones and Coulomb
potential fields) and the new comparative molecular similarity indices analysis (CoMSIA).
Models of comparative statistical significance were obtained. Field contribution maps
were produced for the different models. Due to cutoff settings in the CoMFA fields
and the steepness of the potentials close to the molecular surface, the CoMFA maps
are often rather fragmentary and not contiguously connected. This makes their interpretation
difficult. The maps obtained by the new CoMSIA approach are superior and easier to
interpret. Whereas the CoMFA maps denote regions apart from the molecules where interactions
with a putative environment are to be expected, the CoMSIA maps highlight those regions
within the area occupied by the ligand skeletons that require a particular physicochemical
property important for activity. This is a more significant guide to trace the features
that really matter especially with respect to the design of novel compounds.