Cilengitide was anticipated to be a highly promising potential anti-angiogenic small molecule drug but unfortunately it failed phase III clinical trial in early 2013 (survival rate not passed). Today, there is still not a small molecule αvβ3 integrin drug in use in the clinic, new antagonists were urgently needed to advance the treatment of the αvβ3 integrin related diseases. / Peptide-type antagonists possess unique advantages such as non-accumulative, bio-friendly etc. comparing to other types of antagonists (peptidomimetics, non-peptidic etc.). Cilengitide is one of the peptide-type antagonists and it remains the most successful drug candidate demonstrated. Reinvestigation of the binding between Cilengitide and the αvβ3 integrin is therefore still meaningful. Specifically, the present study will concentrate on revealing the factors responsible for higher binding affinity of Cilengitide, comparing to the parent compound c(RGDfV), c(RADfV) and other N-methylated derivatives of c(RGDfV). Note that c(RADfV) could be also viewed as a methylation product of c(RGDfV) (methylation of side chain of the -G- residue). It is intended that the results of this investigation could provide clear guidance towards future efforts in the design of new peptide αvβ3 integrin antagonists. / Utilizing a novel but successful computational protocol, namely an integrated docking, molecular dynamics simulation and MM_GBSA free energy calculation method, the present thesis found that the binding profile between Cilengitide and the αvβ3 integrin is unique when compared to bindings of other methylation compounds. On the one hand, structural analysis (such as RMSD, ligand structure, hydrogen bond, backbone and side chain orientation) revealed that only c(RGDfV) and Cilengitide substantially retain the binding mode of the parent compound c(RGDfV) (Cilengitide is closer than c(RGDfV)). On the other hand, calculated binding energy results revealed that only c(RGDfV) and Cilengitide bind more strongly than c(RGDfV) to the αvβ3 integrin. Since in experiments only Cilengitide binds more strongly than c(RGDfV), it is therefore believed that both structural and energetic factors are responsible for the high binding affinity of Cilengitide. / Other energetic study revealed that the high binding affinity of Cilengtide compared to c(RGDfV) originates from Coulombic interaction (sum of electrostatic interaction and polar solvation energy), while van der Waals interaction and non-polar solvation energy was not favorable for Cilengitide binding. For the residue contribution, energy changes on the -R- and -G- residues upon methylation were nearly zero. Changes on the -D- and -f- residues were favorable for Cilengitide binding, while change on the -V- residue was not. Total changes on the five residues are favorable however. Pair-wise analysis suggests that interactions of the -D- residue in Cilengitide were very important for the binding, as suggested by its sizeable coupling energies with other residues. Amongst them the coupling between -D- and Mg688 is the most important pair. / In brief, the present study provides a quantitative understanding towards the binding between Cilengitide series ligand and the αvβ3 integrin. Through comparison with bindings between the methylated analogues of c(RGDfV), important features responsible for high binding affinity of Cilengitide were revealed. Some of the results contained in the thesis are in the process of being reported in "C. Yan, S. C. F. Au-Yeung. Investigation of the 'Methyl Effect' in the Cilengitide Binding Ligand Series and Its Implications on Future Integrin Antagonist Design. J. Med. Chem., in preparation (2014)". / Cilengitide是一种曾被高度寄望成为抗血管增生小分子药物的化合物。遗憾的是，2013年初所述化合物没有通过临床三期测试 (存活率不过关)。由于至今临床上仍然没有αvβ3整合素的小分子药物在使用，新的拮抗剂需要被设计出来以推进αvβ3整合素相关疾病的治疗。 / 相比于其它类型的拮抗剂 (类肽物、非肽类等)，多肽型的拮抗剂具有其独特的优点，譬如不积聚、生物友好等。Cilengitide是一种多肽型的拮抗剂，至今为止其仍是已证明的最成功的药物候选。重新研究Cilengitide与αvβ3整合素的结合情况因此仍然具有意义。具体地，本研究将聚焦于揭示相比于母体化合物c(RGDfV)、c(RADfV) 和c(RGDfV) 其它N-甲基化衍生物Cilengitide高亲和性的因素。c(RADfV) 可视为c(RGDfV) 另一甲基化的产物（-G- 残基侧链甲基化）。本研究的结果希望能给未来新型多肽型αvβ3整合素拮抗剂的设计以清晰的指导。 / 通过采用一种新的但颇成功的计算协议，即一种分子对接、分子动力学和MM_GBSA的综合方法，本论文发现相比于上述非Cilengitide的配体，Cilengitide与 αvβ3整合素的结合模式非常独特。一方面，结构分析 (RMSD、配体结构、氢键和骨架及侧链取向) 显示只有c(RGDfV) 与Cilengitide保留了其母体化合物，即c(RGDfV) 的结合模式（Cilengitide比c(RGDfV) 更接近）。另一方面，结合能计算结果显示只有Cilengitide和c(RGDfV) 与αvβ3整合素的结合比母体化合物c(RGDfV) 更强。由于实验上只有Cilengitide的结合强于c(RGDfV)，因此有理由相信结构和能量因素均对Cilengitide高亲和性负责。 / 其它能量研究显示相比于c(RGDfV)，Cilengitide的高亲和性来源于库仑作用 (静电作用和极性溶剂化能的加和)。范德华作用和非极性溶剂化能则对Cilengitide结合不利。残基贡献方面，甲基化后 -R- 和 -G- 的能量变化基本为零；-D- 和 -f- 残基的能量变化则有利于Cilengitide的结合，而 -V- 能量变化则不利。然而这五个残基的总变化对结合是有利的。配对分析结果显示Cilengitide中 -D- 残基的作用对于结合是非常重要的，这从其与其它残基可观的耦合能可以得知。其中，-D- 与Mg688的耦合是最重要的一对。 / 简言之，本研究提供了对Cilengitide系列配体与αvβ3整合素结合的定量理解。通过c(RGDfV) 甲基化后同类物的结合相互间的比较，揭示了负责Cilengitide高亲和性的重要特征。本论文中的一些研究结果正将报道于： / “严长青，欧阳植勋。关于Cilengitide配体系列中“甲基效应”的研究及其对未来αvβ3整合素拮抗剂设计的启示。药物化学杂志，准备中(2014)” / Yan, Changqing. / Thesis Ph.D. Chinese University of Hong Kong 2014. / Includes bibliographical references (leaves 138-146). / Abstracts also in Chinese. / Title from PDF title page (viewed on 18, January, 2017). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_1291929 |
| Date | January 2014 |
| Contributors | Yan, Changqing (author.), Au Yeung, Chik Fun Steve (thesis advisor.), Chinese University of Hong Kong Graduate School. Division of Chemistry. (degree granting institution.) |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography, text |
| Format | electronic resource, electronic resource, remote, 1 online resource (xxiii, 146 leaves) : illustrations (some color), computer, online resource |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons "Attribution-NonCommercial-NoDerivatives 4.0 International" License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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