Pharmacoinformatics exploration of polyphenol oxidases leading to novel inhibitors by virtual screening and molecular dynamic simulation study |
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| Institution: | 1. Department of Biology, College of Natural Sciences, Kongju National University, Gongju 32588, Republic of Korea;2. Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan;3. School of Social Sciences and Psychology, Westren Sydney University, Sydney, New South Wales, Australia;4. MARCS Institute for Brain and Behaviour, Westren Sydney University, Sydney, New South Wales, Australia;1. School of Bio Sciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India;2. School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India;1. Institute of Biological Information Processing: Structural Biochemistry (IBI-7), Forschungszentrum Jülich, 52428 Jülich, Germany;2. Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;3. Multiuser Center for Biomolecular Innovation, IBILCE, Universidade Estadual Paulista (UNESP), São Jose do Rio Preto, SP, Brazil;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria;1. Department of Bioinformatics, Rajiv Gandhi Institute of IT and Biotechnology, Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, India;2. Department of Chemical Technology, University of Calcutta, 92 A.P.C. Road, Kolkata, India;3. Chemistry Department, P. O. Box 84428, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, 11671, Saudi Arabia;4. Department of Chemistry, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia;5. Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom;6. School of Health Sciences, University of Kwazulu-Natal, Westville Campus, Durban, South Africa;7. Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria and National Health Laboratory Service Tshwane Academic Division, Pretoria, South Africa;1. College of Natural Science, Department of Biological Sciences, Kongju National University, Gongju 32588, South Korea;2. Department of Chemistry, Government College University, Lahore 54000, Pakistan;3. Faculty of Pharmacy, Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia;4. Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Level 9, FF3, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia;1. Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan;2. Institute of Molecular Biology and Biotechnology, The University of Lahore, Pakistan;3. Department of Physiology, University of Sindh, Jamshoro, Pakistan;1. Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, PMB LG 77, Legon, Accra, Ghana;2. West African Center for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana;3. Department of Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA;4. Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, P.O. Box LG 581, Legon, Accra, Ghana;5. Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA;6. Department of Virology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, P.O. Box LG 581, Legon, Accra, Ghana |
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| Abstract: | Polyphenol oxidases (PPOs)/tyrosinases are metal-dependent enzymes and known as important targets for melanogenesis. Although considerable attempts have been conducted to control the melanin-associated diseases by using various inhibitors. However, the exploration of the best anti-melanin inhibitor without side effect still remains a challenge in drug discovery. In present study, protein structure prediction, ligand-based pharmacophore modeling, virtual screening, molecular docking and dynamic simulation study were used to screen the strong novel inhibitor to cure melanogenesis. The 3D structures of PPO1 and PPO2 were built through homology modeling, while the 3D crystal structures of PPO3 and PPO4 were retrieved from PDB. Pharmacophore modeling was performed using LigandScout 3.1 software and top five models were selected to screen the libraries (2601 of Aurora and 727, 842 of ZINC). Top 10 hit compounds (C1-10) were short-listed having strong binding affinities for PPO1-4. Drug and synthetic accessibility (SA) scores along with absorption, distribution, metabolism, excretion and toxicity (ADMET) assessment were employed to scrutinize the best lead hit. C4 (name) hit showed the best predicted SA score (5.75), ADMET properties and drug-likeness behavior among the short-listed compounds. Furthermore, docking simulations were performed to check the binding affinity of C1-C10 compounds against target proteins (PPOs). The binding affinity values of complex between C4 and PPOs were higher than those of other complexes (−11.70, −12.1, −9.90 and −11.20 kcal/mol with PPO1, PPO2, PPO3, or PPO4, respectively). From comparative docking energy and binding analyses, PPO2 may be considered as better target for melanogenesis than others. The potential binding modes of C4, C8 and C10 against PPO2 were explored using molecular dynamics simulations. The root mean square deviation and fluctuation (RMSD/RMSF) graphs results depict the significance of C4 over the other compounds. Overall, bioactivity and ligand efficiency profiles suggested that the proposed hit may be more effective inhibitors for melanogenesis. |
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| Keywords: | Polyphenol oxidases (PPOs) Tyrosinase inhibitors Molecular modeling Docking molecular dynamic simulation |
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