Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor
Affiliation:
1. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;2. Department of Chemistry, Hazara University, Mansehra 21120, Pakistan;3. Department of Biochemistry, Abdul Wali Khan University, Mardan 23200, Pakistan;4. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi 75270, Pakistan;1. Department of Physics, Abdul Wali Khan University (AWKUM), Mardan 23200, Pakistan;2. Center of Excellence in Glass Technology and Materials Science (CEGM), Nakhon Pathom Rajabhat University, Nakhon Pathom 73000, Thailand;3. Physics Program, Faculty of Science and Technology, Nakhon Pathom Rajabhat University, Nakhon Pathom 73000, Thailand;4. Department of Physics, Kyungpook National University, Deagu 702-701, Republic of Korea;1. Faculty of Engineering Sciences, GIK Institute of Engineering Sciences and Technology Topi, KPK 23640, Pakistan;2. Department of Physics, Abdul Wali Khan University Mardan, 23200 KPK, Pakistan;3. Department of Electronics, Jinnah College for Women, University of Peshawar, Peshawar 25120, Pakistan;1. Faculty of Engineering Sciences, GIK Institute of Engineering Sciences and Technology, Swabi, Khyber Pakhtunkhwa, Topi 23640, Pakistan;2. Department of Physics, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan;3. Department of Electronics, Jinnah College for Women, University of Peshawar, Peshawar 25120, Pakistan;4. Institute of Chemistry, University of the Punjab, Lahore 54000, Pakistan;1. Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;2. Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA;3. Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54550, Pakistan;4. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan;5. Department of Chemistry, Faculty of Natural and Mathematical Sciences, King’s College London, London WC2R 2LS, UK;6. Chandka Medical College, Larkana, Sindh 77150, Pakistan;7. University of Lahore, Lahore 54550, Pakistan;8. Department of Biochemistry, Abdul Wali Khan University, Mardan, 23200 Khyber Pakhtunkhwa, Pakistan;9. Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science & Technology (NUST), Islamabad 44000, Pakistan;10. Department of Biotechnology and Bioinformatics, International Islamic University, Islamabad 44000, Pakistan;11. Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA;12. Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore 54550, Pakistan;13. Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan;1. School of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, China;2. School of Preclinical Medicine, Shanxi Medical University, Taiyuan 030001, China;3. Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Molecular Science, Shanxi University, Taiyuan 030006, China
Abstract:
Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Among all virtual screening methods structure based docking has received considerable attention. In an attempt to identify new ligands as urease inhibitors, structure-based virtual screening (SBVS) of an in-house database of 10,000 organic compounds was carried out. The X-ray crystallographic structure of Bacillus pasteurii (BP) in complex with acetohydroxamic acid (PDB Code 4UBP) was used as a protein structure. As a starting point, ~10,000 compounds of our in-house database were analyzed to check redundancy and the compounds found repeated were removed from the database. Finally 6993 compounds were docked into the active site of BP urease using GOLD and MOE-Dock software. A remarkable feature of this study was the identification of monastrol, a well-known KSP inhibitor already in clinical trials, as a novel urease inhibitor. The hits identified were further evaluated by molecular docking and on examination of the affinity predictions, twenty-seven analogs of monastrol were synthesized by a multicomponent Biginelli reaction followed by their in vitro screening as urease inhibitors. Finally twelve compounds were identified as new urease inhibitors. The excellent in vitro activity suggested that these compounds may serve as viable lead compounds for the treatment of urease related problems.
