Design of New and Potent Diethyl Thiobarbiturates as Urease Inhibitors: A Computational Approach



Abdul Wadood1*, Muhammad Riaz1, Amir ul Mulk2, Momin Khan2, Sobia Ahsan Haleem3, Sulaiman Shams1, Sahib Gul1, Ayaz Ahmed4, Muhammad Qasim5, Farman Ali6 & Zaheer Ul-Haq7



1Computational Medicinal Chemistry Laboratory, Department of Biochemistry, Abdul Wali Khan University, Mardan, Pakistan; 2Department of Chemistry, Abdul Wali Khan University Mardan, Pakistan; 3National Center of Excellence in Molecular Biology, University Punjab Lahore, Pakistan; 4Department of Biotechnology, Abdul Wali Khan University Mardan, Pakistan; 5Department of Environmental Sciences, Abdul Wali Khan University Mardan, Pakistan; 6Department of Zoology, Abdul Wali Khan University Mardan, Pakistan; 7HEJ, Research Institute of Chemistry, University of Karachi, Karachi, Pakistan


Email; *Corresponding author


Article Type



Received March 27, 2014; Accepted April 03, 2014; Published May 20, 2014



Urease is an important enzyme both in agriculture and medicine research. Strategies based on urease inhibition is critically considered as the first line treatment of infections caused by urease producing bacteria. Since, urease possess agro-chemical and medicinal importance, thus, it is necessary to search for the novel compounds capable of inhibiting this enzyme. Several computational methods were employed to design novel and potent urease inhibitors in this work. First docking simulations of known compounds consists of a set of arylidine barbiturates (termed as reference) were performed on the Bacillus pasteurii (BP) urease. Subsequently, two fold strategies were used to design new compounds against urease. Stage 1 comprised of the energy minimization of enzyme-ligand complexes of reference compounds and the accurate prediction of the molecular mechanics generalized born (MMGB) interaction energies. In the second stage, new urease inhibitors were then designed by the substitution of different groups consecutively in the aryl ring of the thiobarbiturates and N, N-diethyl thiobarbiturates of the reference ligands.. The enzyme-ligand complexes with lowest interaction energies or energies close to the calculated interaction energies of the reference molecules, were selected for the consequent chemical manipulation. This was followed by the substitution of different groups on the 2 and 5 positions of the aryl ring. As a result, several new and potent diethyl thiobarbiturates were predicted as urease inhibitors. This approach reflects a logical progression for early stage drug discovery that can be exploited to successfully identify potential drug candidates.



Urease Inhibitor, Molecular docking, Interaction energy, H. pylori, MOE.



Wadood  et al. Bioinformation 10(5): 299-307 (2014)

Edited by

P Kangueane






Biomedical Informatics



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