Structure based virtual screening of ligands to identify cysteinyl leukotriene receptor 1 antagonist

Abstract

Montelukast and Zafirlukast are known leukotriene receptor antagonists prescribed in asthma treatment. However, these fall short as mono therapy and are frequently used in combination with inhaled glucocorticosteroids with or without long acting beta 2 agonists. Therefore, it is of interest to apply ligand and structure based virtual screening strategies to identify compounds akin to lead compounds Montelukast and Zafirlukast. Hence, compounds with structures having 95% similarity to these compounds were retrieved from NCBI׳s PubChem database. Compounds similar to lead were grouped and docked at the antagonist binding site of cysteinyl leukotriene receptor 1. This exercise identified compounds UNII 70RV86E50Q (Pub Cid 71587778) and Sure CN 9587085 (Pub Cid 19793614) with higher predicted binding compared to Montelukast and Zafirlukast. It is shown that the compound Sure CN 9587085 showed appreciable ligand receptor interaction compared to UNII 70RV86E50Q. Thus, the compound Sure CN 9587085 is selected as a potent antagonist to cysteinyl leukotriene receptor 1 for further consideration in vitro and in vivo validation.

Keywords: Leukotriene antagonists; Molecular docking; Pharmacophoric identification; Virtual screening.

Figure 1

Structure of the 337 residues long cystenyl leukotrine receptor modeled using template structure of Mu-Opioid receptor crystal structure (PDB ID: 4DKLA). Binding site in the protein was detected using Gaussian filter enabled DoGSite server [27]. The N terminal of the protein is extracellular while C terminal lies in the cytoplasmic region of the cell. Lipid environment of membrane is majorly occupied by the polar transmembrane helices (TM1-TM7) and the interconnecting loops between the transmembrane helices are either cytoplasmic or extracellular.

Figure 2

Structure of compound (A) UNII70RV86E50Q (Pubcid: CID: 71587778 ); (B) Sure CN9587085 (Pubcid: 19793614) selected after virtual screening.

Figure 3

A) Interactions of Sure CN 9587085 with cysteinyl leukotrine receptor 1. Residues circled in green participate in van der waals interaction with the ligand while residues in pink forms electrostatic interactions. Hydrogen bonds with bond lengths are shown as blue arrows between ligand and residues Lys 162, Arg 79 and Ser 193; B) Binding pattern of Sure CN 9587085 with cysteinyl leukotrine receptor 1. The pink lines represent various interactions like electrostatic, van der Waals, stearic, hydrogen bonding and hydrophobic interactions that enable energetically favourable binding of the ligand in the cavity.

Figure 4

A) Hydrogen bonds (green dotted lines) formed between Sure CN 9587085 and cysteinyl leukotrine receptor 1; B) The active site of receptor is shown with hydrophobic intensities. The hydrophobic intensities of the binding site ranges from -3.00 (least hydrophobic area - blue shade) to 3.00 (highly hydrophobic area –brown shade).