Molecular Docking and Molecular Dynamics Study of DNA Minor Groove Binders

The fundamental problems in drug discovery are based on the process of molecular recognition by small molecules. The binding specificity of DNA-small molecule is identified mainly by studying the hydrogen bonding and polar interactions. Majority of the minor groove binders and their mechanism of action at the molecular level are not well studied. As these small molecules can act as effective therapeutic agents against many diseases, there is a need to have the detailed mechanistic insights on how they interact with DNA. In this study we have investigated the binding mechanism and stability of the complexes using molecular modeling methods. The molecular docking studies were performed to explore the exact binding sites and affinity inside the DNA minor grove. A 5ns molecular dynamics (MD) simulation for the DNA minor groove binders has been performed using AMBER and GROMACS program. Further, to study the systematic deviation of docked complexes during MD simulation, RMSD as a function of time have been analyzed and it has been found that RMSD variation obtained using AMBER and GROMACS MD simulation are approximately same. The binding free energies between the DNA and minor groove binders were calculated and decomposed by molecular mechanics/generalized born surface area (MM-GBSA) and Molecular Mechanics/Poisson−Boltzmann Surface Area (MM-PBSA) methods. The comparative and systematic analysis presented in this study can provide guidance for the choice of MD methods and the designs of new potent inhibitors targeting DNA.