Molecular Dynamic Simulation and Free Energy of Binding Analysis of Novel Com- pounds from ZINC Database against Wild Type and Engineered Mutant (C1191I, C1191K)DNA Methyltransferase 1

DNA methyltransferase 1 (DNMT1) has emerged as a potential epigenetic target for development of novel anticancer drugs. In the present investigation, we elaborate systematic virtual screening of large collection of natural products as DNMT1 inhibitors. The virtual screening was executed by implementing several docking programs, such as Glide_XP, Autodock, CDOCKER and LigandFit. Screening of 5120 commercially available FDA-approved drugs (mostly phytochemicals) from ZINC database ranked ZINC38517271, ZINC70455592 and ZINC31983781 as top 3 hits with respective Glide score as high as -14.33, -14.18 and -13.08 kcal/mol. In order to investigate the inhibitors that can endure mutations along the active site residues of DNMT1, mutational analysis at Cys1191 residue, followed by docking and molecular dynamic (MD) simulation were carried out. The inhibitors exhibited minimum binding efficiency on substitution to C1191I while binding affinity remained constant for C1191K mutation. The identified novel ligands were subjected to MD simulation, free energy calculation and energy decomposition per residue. The free energy calculation was based on molecular mechanics- Poisson−Boltzmann surface area (MMPBSA) computation. The free binding energy was high for interaction of the novel inhibitors for both wild type (WT) and C1191K mutant DNMT1, while drastic decrease in binding affinity was seen on non-polar substitution of C1191I. The residues, which contribute to higher binding energies, are Phe1145, Glu1168, Met1169, Cys1191/Lys 1191 and Arg1574. Finally the WT/ mutant DNMT1 -inhibitor complexes were analyzed for interaction with hemimethylated DNA. From the results it is evident that interaction of novel inhibitors with both WT and mutant (C1191I, C1191K) DNMT1 decreases the binding affinity for the hemimethylated DNA.