6-(N-benzoylamino)purine as a novel and potent inhibitor of xanthine oxidase: inhibition mechanism and molecular modeling studies.
The inhibition of xanthine oxidase (XO) activity by the purine analogue 6-(N-benzoylamino)purine was evaluated and compared with the standard inhibitor, allopurinol and the parent compound adenine. 6-(N-benzoylamino)purine is a highly potent inhibitor of XO (IC50 = 0.45 microM) and comparable to allopurinol (IC50 = 0.80 microM). Furthermore, 6-(N-benzoylamino)purine neither produced any enzymatic superoxide nor reduced XO by an electron transfer reaction unlike allopurinol. 6-(N-benzoylamino)purine (Ki = 0.0475 microM) is about 10000-fold more potent as a XO inhibitor compared to the only known purine analogue 8-bromoxanthine (Ki = 400 microM). 6-(N-Benzoylamino)purine is a competitive inhibitor of XO and the inhibition was not completely reversed even at 100 microM xanthine concentration. The calculated interaction energy [Ecomplex - (Eligand + Eprotein)] of -30.5, -22.6, and -17.2 kcal/mol, respectively, of 6-(N-benzoylamino)purine, 8-bromoxanthine and the parent compound adenine provided the rationale for the better enzyme inhibitory activity of 6-(N-benzoylamino)purine. To understand the role of the benzamido group in the inhibition process, molecular docking studies were carried out and it was revealed that the hydrogen bonding interactions involving N-7 of the purine ring and the N-H of Arg880, N-H of the purine ring and OH of Thr1010, as well as non-bonded interactions of the benzamido group of 6-(N-benzoylamino)purine with amino acid residues Gly799, Glu802, Phe914, Ala1078, Ala1079 and Glu1261 in the active site of XO play an important role in the stabilization of the E-I complex.
Tamta
Hemlata
H
Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, SAS Nagar, Punjab, India.
Thilagavathi
Ramasamy
R
Chakraborti
Asit K
AK
Mukhopadhyay
Anup K
AK
D000225:Adenine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006860:Hydrogen Bonding; D006861:Hydrogen Peroxide / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*; D014970:Xanthines / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011687:Purines; D014970:Xanthines; D013481:Superoxides; D000493:Allopurinol; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D000225:Adenine