In silico assessment of chronic toxicity of a combination drug namely ‘Olmesartan medoxomil and Hydrochlorothiazide’, marketed in Bangladesh

Abstract

Nowadays combination therapy has become more popular due to their additional effect, synergistic effect and antagonistic effect. Any of these can influence the treatment profile. Combination therapy is used to treat some chronic diseases like diabetes, hypertension, cancer etc. But recently India has banned some fixed dose drug combinations due to their increased chances of adverse drug effects and drug interactions. So it is the time to take a look on the present drug combinations available in Bangladesh. An in silico study may provide important information about their probable toxicities. Drugs available in the combination may deposit slowly in the body and may lead to toxicities. Here an antihypertensive drug combination ‘Olmesartan medoxomil and Hydrochlorothiazide’ had been studied. Olmesartan medoxomil and Hydrochlorothiazide have not been found to comply any similar protein to interact with each other, thus no possible chance of additional toxicity of the combination in case of long term use. At first, using PubChem the ligand was searched for a canonical SMILE. By inputting the canonical SMILE in Protox, a basic information about toxicities was predicted. From Swiss Target Prediction, target proteins responsible for both efficacy and toxicity were identified. These protein structures were downloaded from Protein Data Bank and edited with Flare. Undesired amino acid, ligand–ligand complex, fatty acid, and water molecules were removed by PyMOL. Structurally modified proteins and ligands were inputted in Swiss PDB viewer for energy minimization. Energy minimization is a very important step because unfavorable bond length, bond strength and torsion angle between protein and ligand may interfere with docking procedure. Then docking between Olmesartan medoxomil (ligand) and the proteins responsible for efficacy and toxicity was performed by PyRx. Vina binding affinity provided the value of binding strength between the ligand and the proteins, which determines how strong the bond is. The more negative the vina binding affinity, the stronger the bond. Discovery studio software was used to visualize the docking complexes. Same steps were followed for Hydrochlorothiazide to identify proteins responsible for desired and undesired effects, but no toxic effect was found from protox.