Nucleic acids are the most prominent targets for a number of anticancer, antiviral, antitumor, antiprotozoal and antiparasitic drugs. Some of these drugs are either currently in medicinal usages or under clinical trials. Most of these drugs hold aromatic rings within them i.e., they are the derivatives of aromatic class of compounds. Groove binding and intercalation are the two major drug binding modes with which drugs bind themselves with DNA. Intercalation needs conformational changes in DNA due to the formation of intercalation gap between the DNA base pairs whereas, in contrast, minor groove binders which do not require any conformational changes to the DNA . Major groove of the DNA has a width of 11.7Å and depth of 8.8Å, and therefore it holds multiple sites for intercalation which result in the formation of comparatively stronger bonds. Whereas, the width and depth for minor groove of the DNA are 5.7Å and 7.5Å respectively and hence there is no availability of binding pockets in the vicinity of DNA. Geometrical flexibility is an important parameter of DNA minor groove binders. They tend to acquire crescent shape while binding them to DNA and hence stabilize the complex . The structural arrangement of base pairs gives rise to the architecture of major and minor grooves and the environment of each groove is different at molecular prescriptive. On a statistical note, typically, minor groove binders bind to B-DNA with the higher binding affinity towards AT-rich centers . However, the intercalators are usually geometrically planar molecules with several fused rings, and are usually insert between the adjacent base pairs of DNA duplex by their planar moiety. These interactions are quite strong although the fact that energy is consumed due to the unwinding of the helix and unstacking of the base pairs during complex formation. Hydrophobic interactions between ligand and DNA bases contribute towards the stability of intercalated complexes . DNA minor groove is the target for many anticancer and antitumor drugs. The forces that contribute in DNAminor groove binding are electrostatic forces, van der Waal's interactions, hydrophobic interactions, and hydrogen bonding. Sequence specificity is a major clause in drug-DNA interactions. It has been observed that, minor groove binding drugs show selectivity towards AT rich region, several factors are also responsible for this first is electrostatic potential of AT-rich region is higher than that of GC-filled ones and the second one is that the AT-rich grooves are narrower and deeper than GC ones and thus allowing better binding and interactions. Minor groove of the DNA has alternating A and T bases which allows van der Waals contacts between the drug and DNA however no such contact is observed in GC-rich regions because the geometry of groove is altered by bulky amino groups of guanine bases. In this work, some ligands were taken that were claimed to have antimicrobial activities and were subjected to exhaustive computational studies. Molecular modeling techniques such as DFT, molecular docking, molecular dynamics simulation, and Quantum Mechanical/Molecular Mechanical (QM/MM) calculations have been used for the estimation of binding energies, which was then comparatively studied and evaluations were made to reach conclusions. Molecular docking was first done using AutoDock4 software for identifying the drug binding site followed by molecular dynamics simulation for both the drug-DNA complexes using GROMACS software. Docking revealed that lig-1 was bound in the major groove whereas lig-2 was bound in the minor groove of the DNA. We emphasized to analyze both the binding modes (major as well as minor) via MD & QM/MM calculations. The data obtained from molecular dynamics simulation was analyzed for energy variations, variations in radii of gyrations, variations in number of hydrogen bonds, root mean square deviations and root mean square fluctuations. Further, QM/MM calculations were carried out using the ONIOM scheme of Gaussian09 software by taking several snapshots at time interval of 1ns for the entire molecular dynamics' simulations.