Design,synthesis, biological evaluation and molecular dynamics of LAR inhibitors |
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| Affiliation: | 1. Kerala Forest Research Institute, Peechi, Thrissur, Kerala, India;2. Department of Botany, University College, Thiruvananthapuram, Kerala, India;1. Department of Chemistry, University of Louisiana at Lafayette, P.O. Box 44370, Lafayette, LA 70504, USA;2. The Center for Advanced Computer Studies, University of Louisiana at Lafayette, Lafayette, LA 70504, USA;3. High Performance Computing, 329 Frey Computing Services Center, Louisiana State University, Baton Rouge, LA 70803, USA;1. Department of Biotechnology, Assam University, Silchar, 788011, Assam, India;2. Department of Zoology, Moinul Hoque Choudhury Memorial Science College, Algapur, Hailakandi, 788150, Assam, India;1. Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603 103, India;2. Department of Histopathology, Tata Medical Centre, Kolkata, 700160, India |
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| Abstract: | In this study, firstly, the pharmacophore model was established based on LAR inhibitors. ZINC database and drug-like database were screened by Hypo-1-LAR model, and the embryonic compound ZINC71414996 was obtained. Based on this compound, we designed 9 compounds. Secondly, the synthetic route of the compound was determined by consulting Reaxys and Scifinder databases, and 9 compounds (1a-1i) were synthesized by nucleophilic substitution, Suzuki reaction and so on. Meanwhile, their structures were confirmed by 1H NMR and 13C NMR. Thirdly, the Enzymatic assays was carried out, the biological evaluation of compounds 1a-1i led to the identification of a novel PTP-LAR inhibitor 1c, which displayed an IC50 value of 4.8 μM. At last, molecular dynamics simulation showed that compounds could interact strongly with the key amino acids LYS1350, LYS1352, ARG1354, TYR1355, LYS1433, ASP1435, TRP1488, ASP1490, VAL1493, SER1523, ARG1528, ARG1561, GLN1570, LYS1681, thereby inhibiting the protein activity. This study constructed the pharmacophore model of LAR protein, designed small-molecule inhibitors, conducted compound synthesis and enzyme activity screening, so as to provide a basis for searching for drug-capable lead compounds. |
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| Keywords: | LAR-PTPs Inhibitors MDs Pharmacophore model |
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