MADoSPRO: a new Approach to Molecular Modelling Studies on a Series of DNA Minor Groove Binders

The aim of this work was devoted to develop a method to predict Delta G values for a series of minor groove binders. Starting from a matrix of docking dataset for 10 minor groove binders (known and not) to 20 DNA fragments, with various sequences, it was possible to analyze the interaction modes and to calculate the Delta G value for new derivatives through MADoSPRO procedure. The method allowed, through the QSPR analysis, to characterize the type of interactions in such complexes, that was demonstrated to be related to quantum chemical and electrostatic descriptors, in agreement with the information available in literature on the structural requirements of specific minor groove ligands. Moreover it was possible also to design new ligands with different lengths and enedine spacers to modulate the binding affinity with various nucleotide sequences. It was observed that in some cases it was possible to increase the affinity toward GC base-pairs notoriously not favoured for most of groove binders.