Comparison of the Minimal Steric Difference (MTD) and Comparative Molecular Field Analysis (CoMFA) Methods for Analysis of Binding of Steroids to Carrier Proteins
Tudor Ionel Oprea, Dan Ciubotariu, Traian I. Sulea, Zeno Simon · Quantitative Structure-Activity Relationships · 1993
Abstract Cross validation and results with test series indicate similar predictive power for the CoMFA and the much less CPU‐time consuming MTD method. We present an MTD analysis for the binding of a series of 21 steroids to Corticosteroid Binding Globulin (CBG) and to Testosterone Binding Globulin (TeBG) series previously analyzed by CoMFA. For the construction of the hypermolecule we used crystal structures of available steroids retrieved from the Cambridge Crystallographic Data Center (CCDC) and the COSMIC software for structural manipulation and molecular superposition. The correlation results of MTD were r2 = 0.93 for CBG binding and r2 = 0.85 for TeBG binding. The distribution of cavity and wall vertices of the MTD receptor maps present some similarities with the CoMFA coefficient contour maps. Cross validation results of MTD (50% of data in one subseries and 50% in the second), with r2 = 0.70 for CBG and r2 = 0.72 for TeBG binding, are somewhat better than CoMFA results, r2 = 0.66 and r2 = 0.555 respectively, while CoMFA predictions for a separate series of 10 steroids are better. In CoMFA, the equation derived for the molecule receptor affinity corresponds to molecules which interact with “receptor” atoms in fixed positions by electrostatic and van der Waals 6–12 potentials. Repulsions are thereby very high for some of the van der Waals terms – while in reality the overlapping of the ligand and receptor van der Waals envelopes are circumvented by conformational transitions at lower energy costs. This may explain why the elegant CoMFA method indicates only receptor regions whose occupation by the ligand molecules have a favorable or unfavorable effect upon binding.