a Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMACBD) , Military Institute of Engineering , Praça General Tibúrcio 80, Rio de Janeiro , 22290-270 , Brazil .
J Biomol Struct Dyn. 2014;32(10):1601-12. doi: 10.1080/07391102.2013.830578. Epub 2013 Sep 2.
Smallpox was one of the most devastating diseases in the human history and still represents a serious menace today due to its potential use by bioterrorists. Considering this threat and the non-existence of effective chemotherapy, we propose the enzyme thymidylate kinase from Variola virus (VarTMPK) as a potential target to the drug design against smallpox. We first built a homology model for VarTMPK and performed molecular docking studies on it in order to investigate the interactions with inhibitors of Vaccinia virus TMPK (VacTMPK). Subsequently, molecular dynamics (MD) simulations of these compounds inside VarTMPK and human TMPK (HssTMPK) were carried out in order to select the most promising and selective compounds as leads for the design of potential VarTMPK inhibitors. Results of the docking and MD simulations corroborated to each other, suggesting selectivity towards VarTMPK and, also, a good correlation with the experimental data.
天花是人类历史上最具破坏性的疾病之一，由于其可能被生物恐怖分子利用，今天仍然构成严重威胁。考虑到这一威胁和缺乏有效的化疗药物，我们提出痘苗病毒胸苷酸激酶（VarTMPK）作为一种针对天花的药物设计的潜在靶标。我们首先为 VarTMPK 构建了同源模型，并对其进行了分子对接研究，以研究与牛痘病毒胸苷酸激酶（VacTMPK）抑制剂的相互作用。随后，在 VarTMPK 和人胸苷酸激酶（HssTMPK）中对这些化合物进行了分子动力学（MD）模拟，以选择最有前途和选择性的化合物作为潜在 VarTMPK 抑制剂的先导化合物。对接和 MD 模拟的结果相互证实，表明对 VarTMPK 具有选择性，并且与实验数据具有良好的相关性。
