Hit identification against peptidyl-prolyl isomerase of Theileria annulata by combined virtual high-throughput screening and molecular dynamics simulation approach |
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| Institution: | 1. Yildiz Technical University, Faculty of Chemical and Metallurgical Engineering, Department of Bioengineering, Davutpasa Campus, 34210/Esenler, Istanbul, Turkey;2. Marmara University, Faculty of Arts and Sciences, Department of Chemistry, Goztepe Campus, 34722/Kad?koy, Istanbul, Turkey;3. Marmara University, Faculty of Arts and Sciences, Department of Biology, Goztepe Campus, 34722/Kadikoy, Istanbul, Turkey;4. Manhattan College, Department of Chemistry & Biochemistry, 10471, Riverdale, New York, U.S.A;1. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, United States;2. Department of Chemistry, Davidson College, Davidson, NC 28035, United States;1. Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610075, PR China;2. Department of Pharmacy, Chengdu Women''s and Children''s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, PR China;3. Chengdu Pidu District Hospital of TCM, Chengdu 611730, PR China;4. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China |
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| Abstract: | Theileria annulata secretes peptidyl prolyl isomerase enzyme (TaPIN1) to manipulate the host cell oncogenic signaling pathway by disrupting the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) protein level leading to an increased level of c-Jun proto-oncogene. Buparvaquone is a hydroxynaphthoquinone anti-theilerial drug and has been used to treat theileriosis. However, TaPIN1 contains the A53 P mutation that causes drug resistance. In this study, potential TaPIN1 inhibitors were investigated using a library of naphthoquinone derivatives. Comparative models of mutant (m) and wild type (wt) TaPIN1 were predicted and energy minimization was followed by structure validation. A naphthoquinone (hydroxynaphthalene-1,2-dione, hydroxynaphthalene-1,4-dione) and hydroxynaphthalene-2,3-dione library was screened by Schrödinger Glide HTVS, SP and XP docking methodologies and the docked compounds were ranked by the Glide XP scoring function. The two highest ranked docked compounds Compound 1 (4-hydroxy-3-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxynaphthalene-1,2-dione) and Compound 2 (6-acetyl-1,4,5,7,8-pentahydroxynaphthalene-2,3-dione) were used for further molecular dynamics (MD) simulation studies. The MD results showed that ligand Compound 1 was located in the active site of both mTaPIN1 and wtTaPIN1 and could be proposed as a potential inhibitor by acting as a substrate antagonist. However, ligand Compound 2 was displaced away from the binding pocket of wtTaPIN1 but was located near the active site binding pocket of mTaPIN1 suggesting that could be selectively evaluated as a potential inhibitor against the mTaPIN1. Compound 1 and Compound 2 ligands are potential inhibitors but Compound 2 is suggested as a better inhibitor for mTaPIN1. These ligands could also further evaluated as potential inhibitors against human peptidyl prolyl isomerase which causes cancer in humans by using the same mechanism as TaPIN1. |
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| Keywords: | Peptidyl prolyl isomerase Onkogenic signalling patway Molecular dynamics simulation Structure-based drug design |
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