| Abstract: | Urease is an important enzyme both in agriculture and medicine research. Strategies based on urease inhibition is criticallyconsidered as the first line treatment of infections caused by urease producing bacteria. Since, urease possess agro-chemical andmedicinal importance, thus, it is necessary to search for the novel compounds capable of inhibiting this enzyme. Severalcomputational methods were employed to design novel and potent urease inhibitors in this work. First docking simulations ofknown 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 energyminimization of enzyme-ligand complexes of reference compounds and the accurate prediction of the molecular mechanicsgeneralized born (MMGB) interaction energies. In the second stage, new urease inhibitors were then designed by the substitutionof 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 thereference molecules, were selected for the consequent chemical manipulation. This was followed by the substitution of differentgroups on the 2 and 5 positions of the aryl ring. As a result, several new and potent diethyl thiobarbiturates were predicted asurease inhibitors. This approach reflects a logical progression for early stage drug discovery that can be exploited to successfullyidentify potential drug candidates. |
