title: Structural basis of binding and rationale for the potent urease inhibitory activity of biscoumarins.
abstract: Urease belongs to a family of highly conserved urea-hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and reactive cysteine residue in the active sites. In the current study we examined a series of biscoumarins 1-10 for their mechanisms of inhibition with the nickel containing active sites of Jack bean and Bacillus pasteurii ureases. All these compounds competitively inhibited Jack bean urease through interaction with the nickel metallocentre, as deduced from Michaelis-Menten kinetics, UV-visible absorbance spectroscopic, and molecular docking simulation studies. Some of the compounds behaved differently in case of Bacillus pasteurii urease. We conducted the enzyme kinetics, UV-visible spectroscopy, and molecular docking results in terms of the known protein structure of the enzyme. We also evaluated possible molecular interpretations for the site of biscoumarins binding and found that phenyl ring is the major active pharmacophore. The excellent in vitro potency and selectivity profile of the several compounds described combined with their nontoxicity against the human cells and plants suggest that these compounds may represent a viable lead series for the treatment of urease associated problems.
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa 23200, Pakistan ; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Muhammad Arif
authors.initials: MA
authors.lastname: Lodhi
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa 23200, Pakistan.
authors.forename: Sulaiman
authors.identifier: 0000-0001-7792-1180
authors.initials: S
authors.lastname: Shams
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan ; H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Muhammad Iqbal
authors.initials: MI
authors.lastname: Choudhary
authors.affiliation: Departament de Didàctica de les Ciències Experimentals i la Matemàtica, Universitat de Barcelona, Spain.
authors.forename: Atif
authors.initials: A
authors.lastname: Lodhi
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Saima
authors.initials: S
authors.lastname: Jalil
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Sarfraz Ahmad
authors.initials: SA
authors.lastname: Nawaz
authors.affiliation: H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Khalid Mohammed
authors.initials: KM
authors.lastname: Khan
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan ; Institute of Chemistry, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan.
authors.forename: Sajid
authors.initials: S
authors.lastname: Iqbal
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan ; H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Atta-ur
authors.initials: AU
authors.lastname: Rahman
mesh_terms: D001407:Bacillus / Q000201:enzymology; D001665:Binding Sites; D032449:Canavalia / Q000201:enzymology; D020134:Catalytic Domain; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D058116:Lewis Acids / Q000737:chemistry; D062105:Molecular Docking Simulation; D009532:Nickel / Q000737:chemistry; D011485:Protein Binding; D014508:Urea / Q000737:chemistry* / Q000378:metabolism; D014510:Urease / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D003374:Coumarins; D058116:Lewis Acids; D009532:Nickel; D014508:Urea; D014510:Urease; D003545:Cysteine