Human liver is the largest organ in the body and consists of five-percent body weight (Mita et al 2006). It acts as the primary site of detoxification of synthetic and natural compounds in systemic circulation, thereby performing an essential role in human physiology. Liver toxicity, which is also known as hepatotoxicity, is one of the most problematic conditions that could lead to serious disorders. Liver damage can reach a critical threshold, and the injury may exceed the regeneration capacity and adaptive repair of the liver, hence contributing to progressive liver damage. Throughout the metabolism of drug induced liver injury, liver cells may be injured causing liver toxicity, consequently acute liver failure. Additionally, certain drugs appeared to have an indirect effect in progressing liver toxicity through disrupting the function of the Bile Salt Export Pump (BSEP) transporter. This transporter has a role in eliminating the unconjugated and conjugated bile acids/salts from hepatocyte into the bile 1. Inhibiting the BSEP will cause reduction in the bile salt secretion and therefore accumulation of bile salts in hepatocytes, causing liver damage.
Drug-induced liver injury is a relevant clinical issue, in severe cases ending in liver transplantation. Therefore, measurement of BSEP inhibition by candidate drugs has high importance in drug discovery and development.
Improper functioning of BSEP leads to an accumulation of bile salts within hepatocytes, where bile salts become cytotoxic. If persistent, accumulation of bile salts in hepatocytes will lead to liver disease.
For the past 10 years, drug-induced liver injury, abbreviated to DILI, has become a common reason for safety-related marketing withdrawals (Food and Drug Administration, 2009)2. DILI has been considered to pose a massive economic challenge to the pharmaceutical companies, and cause suffering of patients, as well as the costs of the associated healthcare. The reason behind this economic challenge is the decrease in post-marketing restrictions, approval rates and boxed warnings. Many drugs that result in drug-induced liver injury (DILI) do so in an unpredicted and irregular manner, a condition termed as idiosyncratic events. In clinical trials, compounds that contribute to severe drug-induced liver injury are challenging to detect because of the low incidence rate, hence will appear undetected until the post-marketing monitoring where the drug is available for use to the entire population (Bleibel et al., 2007) 3. Additionally, pre-clinical animal models were found to be insufficient predictors of the BSEP-related liver toxicity, possibly because of differences in bile acid composition between humans and animals, as well as differences in hepatobiliary transporter modulation or constitutive expression 4. Hence, BSEP-mediated liver injury may undergo undetected until the later stages of drug development. Therefore, the early identification of drug-induced liver injury reduces the attrition rate of the drug in pharmaceutical industries.
Descriptors and relationship to BSEP inhibition
In terms of inhibition of BSEP, a previous report has been indicated that many lipophilic drugs are inhibitors of BSEP such as tamoxifen, valinomycin, reserpine, rifamycin SV, cyclosporine A, troglitazone, and paclitaxel (Wang et al., 2003). Cyclosporine A and troglitazone, which are among the most potent known BSEP inhibitors, cause drug-induced cholestasis not only in rats but also in humans (Cadranel et al., 1992; Gitlin et al., 1998; Funk et al., 2001).
add on logS, weight, heavy atoms, volume etc.
MOE (molecular operating environment)
MOE provides a suite of applications for manipulating and analyzing large collections of molecules. Create molecular surfaces and analyze surface properties such as hydrophobic and electrostatic potentials. Analyze surface patches to understand local
hydrophobic and polar properties. Compare multiple structures to understand differences in affinity and structural variability. Highlight potential reactive sites for oxidation and deamidation. Visualize and ranks hot spots using knowledge-based potentials and evaluate the non-linear Poisson-Boltzmann equation to evaluate electrostatic preferences in order to rationalize interactions and potential sites for mutagenesis.
Calculate hundreds of molecular descriptors including topological indices, structural keys, E-state indices, physical properties (such as LogP, molecular weight and molar refractivity), topological polar surface area (TPSA) and CCG’s VSA descriptors [Labute 2003] with wide applicability to both biological activity and ADME property prediction. Use descriptors for classification, clustering, filtering and predictive model construction.
This is an important program used to calculate the molecular descriptors that may be help to predict liver toxicity. It can generate more than 300 descriptors. There are two types of molecular descriptors that can be generated using MOE. These are the 2D molecular descriptors, which include physical properties, atoms, bonds, distances and number of aromatics. Additionally, 3D molecular descriptors, which include energy, pharmacophore, shape and volume. (http://www.chemcomp.com/journal/descr.htm).