Abstract

EXPLORING THE MOLECULAR AND STRUCTURAL MECHANISM FOR DRUG INDUCED HEPATOTOXICITY: A VIRTUAL BASED APPROACH

*Yunusa Abdulmajeed and Buhari, Mujibu

ABSTRACT

Hepatotoxicity implies chemical-driven liver damage. More than 900 drugs have been implicated in causing liver injury and it is the most common reason for a drug to be withdrawn from market. Drug-induced liver injury is responsible for 5% of all hospital admissions and 50% of all acute liver failures. More than 75 percent of cases of idiosyncratic drug reactions result in liver transplantation or death. Systematic and quantitative studies of hepatotoxicity have become increasingly important due to rising concerns of drug induced hepatotoxicity. Drugs frequently interact with more than one target, with hundreds of these targets linked to the side effects of clinically used therapeutics. This is based on the hypothesize that drugs with same side effects are likely to have similar targets. Developing a computational model to predict drug induced hepatotoxicity will provide a screening tool for hepatotoxicity thereby minimizing the number of hepatotoxic drugs released to the market. The study was aimed at exploring the various molecular and structural mechanisms for drug induced hepatotoxicity using computer simulation techniques; pharmacophore studies, PASSONLINE target identification and molecular docking simulation techniques. Hydrogen bond acceptor and hydrophobic interactions were the features common to hepatotoxic drugs, macrophage stimulating factor 1 and glutamate dehydrogenase were the common hepatotoxic targets. The hepatotoxic drugs demonstrated excellent binding affinities against the common targets and superimpose with each other and the co-crystalized ligand in the active pocket of each of the targets. These findings imply that hepatotoxic drugs potentiate the effects of these targets and might be molecular mechanism responsible for the hepatotoxic associated with drugs.

Keywords: Pharmacophore, molecular-docking &drug-induced hepatoxicity.