Targeting the intersubunit cavity of Plasmodium falciparum glutathione reductase by a novel natural inhibitor: Computational and experimental evidence |
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| Affiliation: | 1. School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India;2. Biochemistry and Molecular Biology, Interdisciplinary Research Center, Justus Liebig University, Giessen 35392, Germany;3. Apaji Institute of Mathematics & Applied Computer Technology, Banasthali University, Tonk, Rajasthan 304022, India;4. Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute, Jena 07745, Germany;5. Thematic Unit of Excellence on Computational Materials Science, S. N. Bose National Centre for Basic Sciences, Sector-III, Block – JD, Salt Lake, Kolkata 700098, India;1. College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China;2. Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;3. University of Chinese Academy of Sciences, Beijing 100009, China;1. Departamento de Epidemiologia, Faculdade de Saúde Pública, Universidade de São Paulo, Avenida Dr. Arnaldo 715, CEP 01246-904, São Paulo, Brazil;2. Laboratório de Parasitologia, Instituto Butantan, Avenida Vital Brasil 1500, CEP 05503-900, São Paulo, Brazil;3. Programa de Pós-Graduação em Medicina Tropical da Universidade de São Paulo, Avenida Doutor Enéas de Carvalho Aguiar 470, CEP 05403-000, São Paulo, Brazil;4. Superintendência de Controle de Endemias, Departamento de Controle de Vetores, Rua Rui Barbosa, 1672, CEP 14810-095, São Paulo, Brazil;1. Medicines for Malaria Venture, 1215 Geneva 15, Switzerland;1. Laboratoire de Biologie Evolutive, Ecologie et Gestion des Ecosystèmes, Faculté des Sciences et Techniques, Université Cheikh Anta Diop, B.P. 5005, Dakar, Senegal;2. UMR SPE 6134, CNRS-Université de Corse, Campus Grimaldi Bât 018, 20250 Corte, Corse, France;3. Department of Life Sciences, Natural History Museum, Cromwell Road, London SW7 5DB, United Kingdom |
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| Abstract: | Glutathione reductase (GR), a homodimeric FAD-dependent disulfide reductase, is essential for redox homeostasis of the malaria parasite Plasmodium falciparum and has been proposed as an antimalarial drug target. In this study we performed a virtual screening against PfGR, using the structures of about 170,000 natural compounds. Analysis of the two top-scoring molecules, TTB and EPB, indicated that these ligands are likely to interact with the homodimer intersubunit cavity of PfGR with high binding energy scores of −9.67 and −9.60 kcal/mol, respectively. Both compounds had a lower affinity for human GR due to differences in structure and electrostatic properties. In order to assess the putative interactions in motion, molecular dynamics simulations were carried out for 30 ns, resulting in TTB being more dynamically and structurally favored than EPB. A closely related compound MDPI 21618 was tested on recombinant PfGR and hGR, resulting in IC50 values of 11.3 ± 2.5 μM and 10.2 ± 1.7 μM, respectively. Kinetic characterization of MDPI 21618 on PfGR revealed a mixed-type inhibition with respect to glutathione disulfide (Ki = 9.7 ± 2.3 μM) and an uncompetitive inhibition with respect to NADPH. Furthermore, MDPI 21618 was found to inhibit the growth of the chloroquine-sensitive P. falciparum strain 3D7 with an IC50 of 3.2 ± 1.9 μM and the chloroquine-resistant Dd2 strain with an IC50 of 3.2 + 1.6 μM. In drug combination assays with chloroquine, artemisinin, or mefloquine MDPI 21618 showed an antagonistic action, which might suggest partially overlapping routes of action. This study further substantiates research on PfGR as a potential antimalarial drug target. |
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| Keywords: | Glutathione reductase Inhibitor Malaria Screening |
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