In silico binding analysis and SAR elucidations of newly designed benzopyrazine analogs as potent inhibitors of thymidine phosphorylase |
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| Institution: | 1. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, No.16, Jichang Road, Guangzhou 510405, China;2. Sun Yat-sen University First Affiliated Hospital, No 58, Zhongshan 2nd Road, Guangzhou 510080, China;1. Department of Chemistry, Hazara University, Mansehra, 21120, KP, Pakistan;2. Department of Chemistry, University of Okara, Okara, 56130, Pakistan;3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;4. Department of Zoology, Faculty of Life sciences, University of Okara, Okara, 56130, Pakistan;5. Center for Nanoscience, University of Okara, Okara, 56130, Pakistan;6. Faculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam, Selangor 42300, Malaysia;7. Atta-ur-Rahman Institute for Natural Product Discovery (AuRIns), Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam, Selangor 42300, Malaysia;8. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan |
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| Abstract: | Thymidine phosphorylase (TP) is up regulated in wide variety of solid tumors and therefore presents a remarkable target for drug discovery in cancer. A novel class of extremely potent TPase inhibitors based on benzopyrazine (1–28) has been developed and evaluated against thymidine phosphorylase enzyme. Out of these twenty-eight analogs eleven (11) compounds 1, 4, 14, 15, 16, 17, 18, 19, 20, 24 and 28 showed potent thymidine phosphorylase inhibitory potentials with IC50 values ranged between 3.20 ± 0.30 and 37.60 ± 1.15 μM when compared with the standard 7-Deazaxanthine (IC50 = 38.68 ± 4.42 μM). Structure-activity relationship was established and molecular docking studies were performed to determine the binding interactions of these newly synthesized compounds. Current studies have revealed that these compounds established stronger hydrogen bonding networks with active site residues as compare to the standard compound 7DX. |
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| Keywords: | Benzopyrazine Synthesis Thymidine phosphorylase inhibition Molecular docking SAR |
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