Abul Bashar Ripon Khalipha1, 3*, Shamrat Kumar Paul2, Md. Solayman Hossain1, Pranta Ray1, Md. Lutful Kabir2
1Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj8100, Bangladesh
2 Department of Biochemistry & Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh
3Evergreen Scientific Research Centre, Gopalganj-8100, Bangladesh
Abstract:
“Fenofibrate is a drug from the fibrate class. The levels of blood triglyceride reduced by Fibric acid derivatives which are called fibrates. Nowadays Cardiovascular Disease (CVD) is a major problem worldwide. The use of Fenofibrate helps to reduce cholesterol level among people who are at risk of CVD. It also decreases diabetic retinopathy with diabetes mellitus. It reduces both low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels as the functions of other fibrates. It increases the levels of high[1]density lipoprotein (HDL) and reduces the triglyceride levels. It is also used for the treatment of hypercholesterolemia and hypertriglyceridemia. In structural molecular biology and Computer-Aided Drug Designing (CADD), Molecular Docking is used for ligand-protein docking to predict the binding mode(s) of a ligand with a protein for which three-dimensional structure is known. After successful docking, it finds out the high-dimensional spaces and based on scoring it gives the best candidate from libraries of compounds and propose the hypothesis how that ligand inhibit the target protein. Herein, we report the binding affinity and the nonbonding interactions of Fenofibrate and its modified compounds with the receptor peroxisome proliferator-activated receptor alpha PPARAlpha (5AZT). By using B3LYP/631G (d, p) level of theory the quantum mechanical calculation was done for optimization of the modified drugs. For the evaluation of modified drug’s impact properties, the analysis of charge distribution, dipole moment and thermodynamic properties such as electronic energy, enthalpy and free energy of these modified were successfully performed. Molecular Docking was used for ligand-protein docking to predict the binding mode(s) of these modified ligand with the target proteins and the non-bonded interactions. The results of these calculations gives us the conviction that the drugs whose were modified they are thermodynamically more stable and so some drugs are more chemically reactive than the parent drug. The benzyl-directed modification as well as trichloro-methyl group had given the risen of hydrogen bond significantly. The modified drugs revealed increased binding affinity toward 5AZT. D-CCl3 and D-CF3 showed binding affinities of -8.6 and -9.0 kcal/mol, respectively against 5AZT compared to the binding affinity -8.3 kcal/mol of the parent drug. Significant interactions observed between the drugs and ALA333 and LEU321 residues of 5AZT. Moreover, designed drugs demonstrated improved pharmacokinetic properties. This study disclosed that D-CF3 and D-CCl3 are the best 5AZT inhibitors.