A QSAR and molecular modelling study towards new lead finding: polypharmacological approach to Mycobacterium tuberculosis

• Published in: SAR and QSAR in environmental research 2017-10, Vol.28 (10), p.815-832
• Main Authors: Janardhan, S., John, L., Prasanthi, M., Poroikov, V., Narahari Sastry, G.
• Format: Article
• Language: English
• Subjects: Cell permeability; Dihydrodipicolinate reductase; Docking; Drug resistance; Glucosamine; Molecular modelling; Mycobacterium; Mycobacterium tuberculosis; N-Acetylglucosamine; Permeability; Pharmacology; pharmacophore modelling; Phosphates; Polypharmacology; privileged scaffolds; QSAR; Screening; Structure-activity relationships; Tuberculosis; virtual screening
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2017.1398782

Developing effective inhibitors against Mycobacterium tuberculosis (Mtb) is a challenging task, primarily due to the emergence of resistant strains. In this study, we have proposed and implemented an in silico guided polypharmacological approach, which is expected to be effective against resistant strains by simultaneously inhibiting several potential Mtb drug targets. A combination of pharmacophore and QSAR based virtual screening strategy taking three key targets such as InhA (enoyl-acyl-carrier-protein reductase), GlmU (N-acetyl-glucosamine-1-phosphate uridyltransferase) and DapB (dihydrodipicolinate reductase) have resulted in initial 784 hits from Asinex database of 435,000 compounds. These hits were further subjected to docking with 33 Mtb druggable targets. About 110 potential polypharmacological hits were taken by integrating the aforementioned screening protocols. Further screening was conducted by taking various parameters and properties such as cell permeability, drug-likeness, drug-induced phospholipidosisand structural alerts. A consensus analysis has yielded 59 potential hits that pass through all the filters and can be prioritized for effective drug-resistant tuberculosis. This study proposes about nine potential hits which are expected to be promising molecules, having not only drug-like properties, but also being effective against multiple Mtb targets.