Investigation of the Behaviors of Some Newly Designed Ligands in the Epstein Barr EBNA1/DNA Binding Domain by MD Simulations and Binding Free Energy Calculations

Abstract The Epstein‐Barr nuclear antigen 1 requires DNA binding to function. Since no Food and Drug Administration‐approved drugs exist to combat with Ebstein‐Barr virus, the study aims to investigate the binding properties of formerly designed ligands in dynamic environment. Thus, in addition to five ligands, study includes molecular dynamics studies of apo‐protein and DNA‐protein complex. The RMSD plots of ligand‐protein complexes revealed that while systems are reached stable states the extended loops of protein are more flexible in ligand‐protein complexes than in DNA‐protein complex. Among the ligands, B288 showed best binding properties with a binding free energy value of −58.63 kcal mol −1 which is followed by B183 with the value of −58.24 kcal mol −1 . It is defined that designed ligands B175, B183, and B288 are more favorable in blocking DNA‐protein binding than Z067 and Z108 ligands obtained from ZINC15 database. The study revealed that the binding of DNA to the EBNA1 antigen can be prevented by targeting the studied binding site of protein. Moreover, the molecular dynamics studies demonstrated the extended loop of protein which wraps up DNA closely is distorted by the ligands, which may also hamper binding of DNA to protein.