title: Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits.
abstract: In recent years, xanthine oxidase has emerged as an important target not only for gout but also for cardiovascular and metabolic disorders involving hyperuricemia. Contrary to popular belief, recent clinical trials with uricosurics have demonstrated that enhanced excretion of uric acid is, by itself, not adequate to treat hyperuricemia; simultaneous inhibition of production of uric acid by inhibition of xanthine oxidase is also important. Virtual screening of in-house synthetic library followed by in vitro and in vivo testing led to the identification of a novel scaffold for xanthine oxidase inhibition. In vitro activity results corroborated the results from molecular docking studies of the virtual screening hits. The isocytosine scaffold maintains key hydrogen bonding and pi-stacking interactions in the deep end of the xanthine-binding pocket, which anchors it in an appropriate pose to inhibit binding of xanthine and shows promise for further lead optimization using structure-based drug design approach.
authors.affiliation: Discovery Informatics, Piramal Healthcare Limited, Goregaon (E), Mumbai 400 063, Maharashtra, India. chandrika.rao@piramal.com
authors.forename: Chandrika
authors.initials: C
authors.lastname: B-Rao
authors.forename: Asha
authors.initials: A
authors.lastname: Kulkarni-Almeida
authors.forename: Kamlesh V
authors.initials: KV
authors.lastname: Katkar
authors.forename: Smriti
authors.initials: S
authors.lastname: Khanna
authors.forename: Usha
authors.initials: U
authors.lastname: Ghosh
authors.forename: Ashish
authors.initials: A
authors.lastname: Keche
authors.forename: Pranay
authors.initials: P
authors.lastname: Shah
authors.forename: Ankita
authors.initials: A
authors.lastname: Srivastava
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Korde
authors.forename: Kumar V S
authors.initials: KV
authors.lastname: Nemmani
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Deshmukh
authors.forename: Amol
authors.initials: A
authors.lastname: Dixit
authors.forename: Manoja K
authors.initials: MK
authors.lastname: Brahma
authors.forename: Umakant
authors.initials: U
authors.lastname: Bahirat
authors.forename: Lalit
authors.initials: L
authors.lastname: Doshi
authors.forename: Rajiv
authors.initials: R
authors.lastname: Sharma
authors.forename: H
authors.initials: H
authors.lastname: Sivaramakrishnan
mesh_terms: D000818:Animals; D003198:Computer Simulation; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D033461:Hyperuricemia / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D010094:Oxonic Acid / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C093270:isocytosine; C489337:potassium oxonate; D010094:Oxonic Acid; D003596:Cytosine; D014969:Xanthine Oxidase