Insilico studies on anthrax lethal factor inhibitors: Pharmacophore modeling and virtual screening approaches towards designing of novel inhibitors for a killer

Bacillus anthracis is a causative organism of anthrax. The main reason to use anthrax as a bioweapon is the combination of the spore's durability and the lethal toxaemia of the vegetative stage. In anthrax infection, lethal factor (LF) is playing crucial role in causing cell death, by inhibiting pathways that rely on this kinase family. The combination of vaccine and antibiotics is preferred as an effective treatment for this target. Till date, no small molecule inhibitor is identified as a drug on the target. In this study, we have performed pharmacophore modeling and docking studies to identify a novel small molecule inhibitor to target the Anthrax LF. The best pharmacophore model is used to screen ∼2 M drug-like small molecule database and yielded 2543 hits. Docking studies of the pharmacophore hits on to the active site of Anthrax LF resulted 120 structurally diverse hits. Out of 120 hits, based on synthetic feasibility, 17 hits are selected for further synthesis and pharmacological screening. In due course, we will publish the updated results.

Bacillus anthracis is a rod shaped Gram-positive bacteria used as a bioweapon, the main cause of anthrax virulence is the combination of the spore's durability and the lethal toxemia of the vegetative stage. A 3D chemical featured based pharmacophore model was developed using Catalyst HypoGen program with a training set of 24 diverse classes of anthrax lethal factor inhibitors. The best pharmacophore model (Hypo 1) consisted of two hydrogen bond acceptors, two hydrophobic features. Based on the structural novelty and selectivity index, we have suggested few inhibitors for further synthesis and pharmacological screening.Figure optionsDownload high-quality image (129 K)Download as PowerPoint slide