QSAR and molecular modelling studies on B-DNA recognition of minor groove binders

Aromatic bisamidines have been proved to be efficient compounds against Leishmania spp. and Pneumocystis carinii, Although the mode of action is still not known, these molecules are supposed to be DNA minor groove binders (MGBs). This paper describes a molecular modelling study for a set of MGBs in order to rank them through their complementarity to the Dickerson Drew Dodecamer (DDD) according to their interaction energies with B-DNA. A comparative molecular field analysis (CoMFA) has shown the importance of relatively bulky positively charged groups attached to the MGB aromatic rings. and small and negatively charged substituents into the middle chain. Models were obtained for DNA denaturation related to H-bonding processes of binding modes. Validation of the model demonstrated the robustness of CoMFA in terms of independent test set of similar MGBs. GRID results allotted bioisosteric substitution of -O- by -NH- in furan ring of furamidine and related compounds as being capable to enhance the binding to DDD. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All rights reserved.