Bicyclo[1.1.1]Pentane as Phenyl Substituent in Atorvastatin Drug to improve Physicochemical Properties: Drug-likeness, DFT, Pharmacokinetics, Docking, and Molecular Dynamic Simulation

Abstract

Hyperlipidemia influences on numerous diseases, such as atherosclerosis, hypertension, and diabetes mellitus, however it still treatable. Atorvastatin is one of the most common statins; yet, it has poor solubility due to the three phenyl rings, which lead to low bioavailability issues. Herein, we used bicyclo [1.1.1] pentane a benzene bioisostere as a replacement for these phenyl groups. In total, seven analogous 1a, 1b, 1c, 2a, 2b, 2c, and 3 were designed and investigated theoretically. Their drug-likeness, physicochemical properties, bioactivity, and pharmacokinetics properties were reported and analyzed. Further DFT calculations at CAM-B3LYP/6-31+g in water were used to report the electronic properties and thermodynamic properties of the suggested analogues. Docking studied were conducted to mimic the interactions of the new derivatives with the active site of HMG-CoA reductase. Since docking results are not reliable, molecular dynamic simulations were carried out on analogous with the best docking score. Finally, binding free energy using MM-GBSA was calculated from the MD trajectories, reveals that compound 1a has promising properties as a drug with a docking score of -8.99 kcal/mol and MM-GBSA of -45.35kcal/mol