Kumalo Hezekiel M, Bhakat Soumendranath, Soliman Mahmoud E
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
Division of Biophysical Chemistry, Lund University, P.O. Box 124, SE-22100, Lund, Sweden.
Chem Biol Drug Des. 2015 Nov;86(5):1131-60. doi: 10.1111/cbdd.12582. Epub 2015 Jun 11.
There are over 100 different types of cancer, and each is classified based on the type of cell that is initially affected. If left untreated, cancer can result in serious health problems and eventually death. Recently, the paradigm of cancer chemotherapy has evolved to use a combination approach, which involves the use of multiple drugs each of which targets an individual protein. Inhibition of heat-shock protein 90 (Hsp90) is one of the novel key cancer targets. Because of its ability to target several signaling pathways, Hsp90 inhibition emerged as a useful strategy to treat a wide variety of cancers. Molecular modeling approaches and methodologies have become 'close counterparts' to experiments in drug design and discovery workflows. A wide range of molecular modeling approaches have been developed, each of which has different objectives and outcomes. In this review, we provide an up-to-date systematic overview on the different computational models implemented toward the design of Hsp90 inhibitors as anticancer agents. Although this is the main emphasis of this review, different topics such as background and current statistics of cancer, different anticancer targets including Hsp90, and the structure and function of Hsp90 from an experimental perspective, for example, X-ray and NMR, are also addressed in this report. To the best of our knowledge, this review is the first account, which comprehensively outlines various molecular modeling efforts directed toward identification of anticancer drugs targeting Hsp90. We believe that the information, methods, and perspectives highlighted in this report would assist researchers in the discovery of potential anticancer agents.
癌症有100多种不同类型，每种类型都是根据最初受影响的细胞类型进行分类的。如果不进行治疗，癌症会导致严重的健康问题并最终导致死亡。最近，癌症化疗的模式已经演变为采用联合治疗方法，即使用多种药物，每种药物针对一种特定的蛋白质。抑制热休克蛋白90（Hsp90）是新型的关键癌症靶点之一。由于其能够靶向多种信号通路，Hsp90抑制已成为治疗多种癌症的有效策略。分子建模方法和技术已成为药物设计和发现流程中实验的“紧密伙伴”。已经开发出了广泛的分子建模方法，每种方法都有不同的目标和结果。在本综述中，我们提供了一个最新的系统概述，介绍了为设计作为抗癌药物的Hsp90抑制剂而实施的不同计算模型。虽然这是本综述的主要重点，但本报告还涉及了不同的主题，如癌症的背景和当前统计数据、包括Hsp90在内的不同抗癌靶点，以及从实验角度（如X射线和核磁共振）看Hsp90的结构和功能。据我们所知，本综述是第一篇全面概述针对鉴定靶向Hsp90的抗癌药物的各种分子建模工作的文章。我们相信，本报告中突出的信息、方法和观点将有助于研究人员发现潜在的抗癌药物。
