Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 9; pp. 2930 - 2939
• Main Authors: B-Rao, Chandrika, Kulkarni-Almeida, Asha, Katkar, Kamlesh V., Khanna, Smriti, Ghosh, Usha, Keche, Ashish, Shah, Pranay, Srivastava, Ankita, Korde, Vaidehi, Nemmani, Kumar V.S., Deshmukh, Nitin J., Dixit, Amol, Brahma, Manoja K., Bahirat, Umakant, Doshi, Lalit, Sharma, Rajiv, Sivaramakrishnan, H.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.05.2012; Elsevier
• Subjects: Animals; Biological and medical sciences; Clinical trials; Computer Simulation; Cytosine - analogs & derivatives; Cytosine - chemical synthesis; Cytosine - chemistry; Cytosine - pharmacology; Docking; Drug development; drugs; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Excretion; Gout; Hit identification; Hydrogen bonding; Hyperuricemia; Hyperuricemia - chemically induced; Hyperuricemia - drug therapy; Isocytosine; Male; Medical sciences; metabolic diseases; Metabolic disorders; Oxonic Acid - pharmacology; Oxonic Acid - toxicity; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; scaffolds; screening; Structure-Activity Relationship; Uric acid; Virtual screening; Xanthine; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism; Xanthine oxidase inhibitors; Xanthine oxidase inhibitors; ip; Isocytosine; Virtual screening; Hit identification; AUC; XOI; PASS; XO; Docking; XDH; po; Mo-Pt; Purine derivatives; Enzyme; Enzyme inhibitor; Molecular interaction; Modeling; Structure activity relation; Molecular model; Xanthine oxidase; Xanthine derivatives; Oxidoreductases
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.03.019

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.