An in silico DNA binding investigation using DFT, molecular docking and molecular dynamics simulation on mono and tetra acetylated derivatives of quinalizarin to enable a comparison with experimental DNA binding data

Abstract

Following dissociation of phenolic–OH, quinalizarin generates anions that face repulsion from DNA posing a challenge to its use as an alternative to anthracyclines. An earlier attempt to prevent anion formation by converting all –OH groups to acetyl units had resulted in increased binding with DNA. Although such increase in binding with DNA compared to quinalizarin was observed, owing to a simultaneous increase in steric bulk, a doubt had remained as to whether it was a true manifestation of acetylation. The suspicion being, whether increase in binding constant overcoming repulsion was offset in any way by increase in steric bulk. This in silico DNA binding investigation aims to realize what would be the outcome if one exclusively acetylates the –OH responsible for mono-anion formation. Not having experimental binding information on mono-acetylated species, DNA binding was tried by an in silico approach. Analysis reveals tetra-acetylated quinalizarin was better than the mono-acetylated form; increase due to groove binding, rather than by intercalation being the correct manifestation. Three forms of quinalizarin and the standard drug doxorubicin were investigated by a general DNA model (PDBID:1BNA) and subsequently by intercalation specific (PDBID:1Z3F) and groove binding specific (PDBID:101D) models. ADMET profiles for drug-like properties were done. Information from in silico analysis suggest simpler analogues of anthracyclines are economical and acetylation of all –OH groups of quinalizarin is biologically significant.