New molecular scaffolds for the design of Mycobacterium tuberculosis type II dehydroquinase inhibitors identified using ligand and receptor based virtual screening.
Using ligand and receptor based virtual screening approaches we have identified potential virtual screening hits targeting type II dehydroquinase from Mycobacterium tuberculosis, an effective and validated anti-mycobacterial target. Initially, we applied a virtual screening workflow based on a combination of 2D structural fingerprints, 3D pharmacophore and molecular docking to identify compounds that rigidly match specific aspects of ligand bioactive conformation. Subsequently, the resulting compounds were ranked and prioritized using receptor interaction fingerprint based scoring and quantitative structure activity relationship model developed using already known actives. The virtual screening hits prioritized belong to several classes of molecular scaffolds with several available substitution positions that could allow chemical modification to enhance binding affinity. Finally, identified hits may be useful to a medicinal chemist or combinatorial chemist to pick up the new molecular starting points for medicinal chemistry optimization for the design of novel type II dehydroquinase inhibitors.
Kumar
Ashutosh
A
Molecular and Structural Biology Division, Central Drug Research Institute, Lucknow, 226 001, India.
Siddiqi
Mohammad Imran
MI
Miertus
Stanislav
S
D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D003198:Computer Simulation; D015195:Drug Design; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors*; D008024:Ligands; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D008024:Ligands; D006836:Hydro-Lyases; C020000:3-dehydroquinate dehydratase