Pharmacophore based virtual screening, synthesis and SAR of novel inhibitors of Mycobacterium sulfotransferase

• Published in: Bioorganic & medicinal chemistry letters 2015-02, Vol.25 (3), p.701-707
• Main Authors: Saha, Rikta, Tanwar, Omprakash, Alam, M. Mumtaz, Zaman, M.S., Khan, Shah A., Akhter, Mymoona
• Format: Article
• Language: English
• Subjects: Algorithms; Anti-tubercular agents; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Binding Sites; Catalytic Domain; Databases, Factual; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hydrogen Bonding; Molecular Docking Simulation; Mycobacterium; Mycobacterium - drug effects; Mycobacterium - enzymology; Pharmacophore mapping; Structure-Activity Relationship; Sulfotransferase; Sulfotransferases - antagonists & inhibitors; Sulfotransferases - metabolism; Virtual screening
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.11.079

[Display omitted] A planned 3D-pharmacophore mapping was carried out on the basis of chemical features associated with known Stf0 inhibitors. Four models (model 1–4) were obtained after GASP (Genetic Algorithm Similarity Program) refinement of seven models (D-1 to D-7) generated by using DISCOtech. The selected GASP model-1 has two hydrogen bond acceptor, two hydrogen bond donor and four hydrophobic points. This model was used for virtual screening (VS) of large public databases along with in house generated knowledge base database. VS followed by docking of selected compounds on Stf0 active site was carried and pose analysis done. Seven hits were identified after all the computational studies, of which 2 hits were synthesized along with their analogs and evaluated for antitubercular activity. IH-45 was found promising after in vitro assay.