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

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Title	Design of New and Potent Diethyl Thiobarbiturates as Urease Inhibitors: A Computational Approach
Authors	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
Affiliation	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	awadood@awkum.edu.pk; *Corresponding author
Article Type	Hypothesis
Date	Received March 27, 2014; Accepted April 03, 2014; Published May 20, 2014
Abstract	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.
Keywords	Urease Inhibitor, Molecular docking, Interaction energy, H. pylori, MOE.
Citation	*Wadood et al.* Bioinformation 10(5): 299-307 (2014)
Edited by	P Kangueane
ISSN	0973-2063
Publisher	Biomedical Informatics
License	This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.