Minimal topological difference method biological activities

The importance of molecular stereochemistry for biological activity was recognized 100 years ago, by Emil Fisher, with his lock and key theory for enzymatic reactions (Motoc 1983). The steric fit of dmg molecule (L-ligand) with its target (usually, receptor, R) depends upon both the shape of the biological receptor and the shape of ligand molecule. MTD (minimal topological difference) method takes into... 

Results from CoMFA studies have been compared with those from Hansch analyses [38, 1019 — 1023] and the minimal topological difference (MTD) method [1024]. Examples for the comparison of Hansch equations with CoMFA studies are e.g. the papain hydrolysis of N-(X-benzoyl)glycine pyridyl esters (60) (eqs. 204, 205 Zn = PLS component n of the corresponding field compare chapter 7.1) [1019, 1020], the emulsin-catalyzed hydrolysis of phenyl-P-D-glucosides [1020], the mutagenic activities of substituted (o-phenylenediamine)platinum dichlorides [1020], dihydrofolate reductase (DHFR) inhibition [1020], and some other biological activities [38, 1021—1023]. 

In this chapter we presented two structural measures of molecular shape that can be used as predictor variables in MLR (multiple linear regression) analysis of structure-activity studies - cylindrical (8,G) and ovality ( in, i = 1,2,3) molecular descriptors - and two inexpensive overlapping methods useful for quick receptor mapping - MTD (minimal topological difference) and MVD (minimal volume difference). A subsequent statistical analysis of QSAR models developed with these shape molecular descriptors explained well the variance in the observed reactivity data (8 descriptor of cylindrical shape) and biological activity of retinoids (MTD) and sulfonamides (MVD). 

FIGURE2.21 Generic worldofthequantitativestrocture-activity/property relationships-QSA(P)R - through classical, 3D, decisional and orthogonal methods of multivariate analysis of the chemical-biological interactions. In scheme, MSD-MTD, CoMFA, and PCA stand for the minimal steric difference-minimal topological difference , comparative molecular field analysis and principal component analysis , respectively after (Putz Lacrama, 2007). 

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