Advances in In-Silico based Predictive In-Vivo Profiling of Novel Potent β-Glucuronidase Inhibitors

Abstract

Background: Intestinal β-glucuronidase enzyme has a significant importance in colorectal carcinogenesis. Specific inhibition of the enzyme helps prevent immune reactivation of the glucuronide- carcinogens, thus protecting the intestine from ROS (Reactive Oxidative Species) mediatedcarcinogenesis.

Objectives: Advancement in In-silico based techniques has provided a broad range of studies to carry out the drug design and development process smoothly using SwissADME and BOILED-Egg tools.

Methods: In our designed case study, we used SwissADME and BOILED-Egg predictive computational tools to estimate the physicochemical, human pharmacokinetics, drug-likeness, medicinal chemistry properties and membrane permeability characteristics of our recently In-vitro evaluated novel β-Glucuronidase inhibitors.

Results: Out of the eleven screened potent inhibitors, compound (8) exhibited excellent bioavailability radar against the six molecular descriptors, good (ADME) Absorption, Distribution, Metabolism and Excretion along with P-glycoprotein, CYP450 isozymes and membranes permeability profile. On the basis of these factual observations, it is to be predicted that compound (8) can achieve in-vivo experimental clearance efficiently, Therefore, in the future, it can be a drug in the market to treat various disorders associated with the overexpression of β-Glucuronidase enzyme such as various types of cancer, particularly hormone-dependent cancer such as (breast, prostate, and colon cancer). Moreover, other compounds (1-7, & 9-11), have also shown good predictive pharmacokinetics, medicinal chemistry, BBB and HIA membranes permeability profiles with slight lead optimization to obtain improved results.

Conclusion: In consequence, in-silico based studies are considered to provide robustness for a rational drug design and development approach to avoid the possibility of failures of drug candidates in the later stages of drug development phases. The results of this study effectively reveal the possible attributes of potent β-Glucuronidase inhibitors, for further experimental evaluation.

Keywords: BOILED-Egg; Blood Brain Barrier (BBB); Colorectal carcinogenesis; Druglikeness; Human intestinal absorption (HIA); Pharmacokinetics; SwissADME; β-Glucuronidase enzyme..