Structure based pharmacophore study to identify possible natural selective PARP-1 trapper as anti-cancer agent |
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| Institution: | 1. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Pondicherry, India;2. Postgraduate and Research Department of Botany, Arignar Anna Government Arts College, Villupuram, Tamil Nadu, India;1. Department of Chemistry, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, India;2. Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad 500 078, Telangana, India;3. Department of Bioinformatics, Pondicherry University, Pondicherry 605014, India;1. Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India;2. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, B.S. 10/1, Janakipuram Extension, Sitapur Road, Lucknow 226031, India;3. Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;4. Architecture et Fonction des Macromolécules Biologiques, CNRS, Aix-Marseille Université, F-13288 Marseille, France;5. USC1408 Architecture et Fonction des Macromolécules Biologiques, Institut National de la Recherche Agronomique, F-13288 Marseille, France;6. Sorbonne Universités, CNRS, Integrative Biology of Marine Models (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France;12. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada;8. Department of Botany, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada;9. Department of Biological Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia |
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| Abstract: | Inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) has turned out an innovative approach for cancer therapy due to its involvement in DNA repair pathways. Although several potent PARP-1 inhibitors have been identified, they exhibit high toxicity, resistivity and diverse pharmacological profile in clinical trials, which necessitate for extensive investigation and development of selective inhibitors. Therefore, the study aimed to identify selective natural PARP-1 inhibitors to reduce toxicity and resistivity with high potency. Accordingly, the combined approach of structure-based pharmacophore and molecular docking study was performed. Hence, the two hits (SN00167272 and STOCK1N-92279) were identified to have all the pharmacophoric features that showed interaction with key residues (Gly863, Ser904, Tyr896, and Tyr907) and least conserved residues (Tyr889 and Asp766). Additionally, these inhibitors represented interactions with unique selective residues (Asp756, Val762, Glu763 and Val886) and exhibited strong interaction with PARP-1 through binding free energy and molecular dynamics study. Hence, the identified hits could further considered for experimental investigations as they may reduce off-target and resistivity of currently available inhibitors and developed as potential anti-cancer agents in the future. Also, the study provides a specific structural insight which could further help to design selective and potent PARP-1 inhibitors. |
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| Keywords: | DNA repair and cancer Pharmacophore modeling Selective PARP-1 trapper Molecular dynamics Binding free energy Per-residue energy decomposition |
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