Bioinformatics & Medical Informatics Team, Biomedical Research Foundation, Academy of Athens, Soranou Efessiou 4, Athens 11527, Greece.
Laboratory of Biology, University of Athens School of Medicine, Greece; Cell and Gene Therapy Laboratory, Biomedical Research Foundation, Academy of Athens, Soranou Efessiou 4, Athens 11527, Greece.
Genomics. 2014 Jan;103(1):107-13. doi: 10.1016/j.ygeno.2013.11.008. Epub 2013 Dec 5.
In the present study, an outline is proposed that may lead to specific drug design targeting of the Trypanosoma brucei DNA Topoisomerase IB. In this direction, an unequivocally specific platform was designed for the development of selective modulators. The designed platform is focused on the unique structural and catalytic features of the enzyme. Extensive phylogenetic analysis based on all available published genomes indicated a broad distribution of DNA topoisomerases across eukaryotic species and revealed structurally important amino acids which could be assigned as potentially strong contributors to the regulation of the mechanism of the T. brucei DNA Topoisomerase IB. Based on the above, we propose a comprehensive in silico 3D model for the structure of the T. brucei DNA Topoisomerase IB. Our approach provides an efficient intergraded platform with both evolutionary and structural insights for the rational design of pharmacophore models as well as novel modulators as the anti-T. brucei DNA Topoisomerase IB agents with therapeutic potential.
在本研究中，提出了一个可能导致针对布鲁氏锥虫 DNA 拓扑异构酶 IB 的特定药物设计的纲要。在这个方向上，为开发选择性调节剂设计了一个明确的特异性平台。该平台专注于酶的独特结构和催化特征。基于所有可用已发表基因组的广泛系统发育分析表明，DNA 拓扑异构酶在真核生物物种中广泛分布，并揭示了结构上重要的氨基酸，这些氨基酸可能被认为是调节布鲁氏锥虫 DNA 拓扑异构酶 IB 机制的潜在重要贡献者。基于上述内容，我们提出了一种针对布鲁氏锥虫 DNA 拓扑异构酶 IB 结构的全面的计算机 3D 模型。我们的方法提供了一个高效的综合平台，具有进化和结构方面的见解，可用于合理设计药效团模型以及新型调节剂，作为具有治疗潜力的抗布鲁氏锥虫 DNA 拓扑异构酶 IB 药物。
