痘病毒胸苷酸激酶抑制剂作为抗天花新型选择性药物的设计
Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox.
作者信息
Guimarães Ana P, de Souza Felipe R, Oliveira Aline A, Gonçalves Arlan S, de Alencastro Ricardo B, Ramalho Teodorico C, França Tanos C C
机构信息
Department of Chemistry, Federal University of Viçosa, Anenida P.H. Rolfs, S/N°, Centro, 36570-000 Viçosa, MG, Brazil; Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Praça General Tiburcio 80, Urca, 22290-270 Rio de Janeiro, RJ, Brazil.
Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Praça General Tiburcio 80, Urca, 22290-270 Rio de Janeiro, RJ, Brazil.
出版信息
Eur J Med Chem. 2015 Feb 16;91:72-90. doi: 10.1016/j.ejmech.2014.09.099. Epub 2014 Oct 13.
Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK.
最近，我们构建了天花病毒胸苷酸激酶（VarTMPK）的同源模型，并将其作为抗天花药物设计的新靶点。在本研究中，我们以抗病毒药物西多福韦和阿昔洛韦作为参考化合物，挑选了11种化合物作为VarTMPK抑制剂药物设计的先导化合物。这些化合物与VarTMPK和人胸苷酸激酶（HssTMPK）相互作用的对接和分子动力学（MD）研究表明，它们竞争底物的结合区域，并据此提出了10种新型VarTMPK抑制剂的结构。这些化合物在VarTMPK和HssTMPK中的进一步对接和MD模拟表明，10种中有9种是VarTMPK的潜在选择性抑制剂。
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