title: A multilayer screening approach toward the discovery of novel Pf-DHFR inhibitors.
abstract: A small yet diverse xanthone library was build and computationally docked against wild type Pf-DHFR by Molegro Virtual Docker (MolDock). For analysis of results an integrated approach based on re-ranking, scaling (based on heavy atom counts), pose clustering and visual inspection was implemented. Standard methods such as self-docking (for docking), EF analysis, average rank determinations (for size normalization), and cluster quality indices (for pose clustering) were used for validation of results. Three compounds X5, X113A and X164B displayed contact footprints similar to the known inhibitors with good scores. Finally, 16 compounds were extracted from ZINC data base by similarity based screening, docking score and drug/lead likeness. Out of these 16 compounds, 11 displayed very close contact footprints to experimentally known inhibitors, indicating there potential utility in further drug discovery efforts.
authors.affiliation: Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bagchi
authors.affiliation: Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, India. Electronic address: anujsharma.mcl@gmail.com.
authors.forename: Anuj
authors.initials: A
authors.lastname: Sharma
mesh_terms: D019992:Databases as Topic; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000302:isolation & purification; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000302:isolation & purification*; D006027:Glycosides / Q000737:chemistry* / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000623335:1,3,7-trihydroxy-2-(2-hydroxy-3-methylbut-3-en-1-yl)-4-(3-methylbut-2-en-1-yl)-9H-xanthen-9-one; C000623334:6-methoxy-3aH-furo(3',2'-4,5)furo(2,3-c)xanthen-7(12cH)-one; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D006027:Glycosides; D006576:Heterocyclic Compounds, 4 or More Rings; C000623336:X164B compound; D044004:Xanthones; D013762:Tetrahydrofolate Dehydrogenase
keywords: Contact footprint; Docking; MolDock; Re-ranking; Size normalization