Isfahani Maryam Beheshti, Mahnam Karim, Seyedhosseini-Ghaheh Hooria, Sadeghi Hamid Mir Mohammad, Khanahmad Hossein, Akbari Vajihe, Varshosaz Jaleh
Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Faculty of Science, Department of Biology, Shahrekord University, Shahrekord, Iran.
Res Pharm Sci. 2023 Nov 23;18(6):626-637. doi: 10.4103/1735-5362.389950. eCollection 2023 Dec.
Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 25% of breast cancer patients; therefore, its inhibition is a therapeutic target in cancer treatment.
In this study, two new variants of designed ankyrin repeat proteins (DARPins), designated EG3-1 and EG3-2, were designed to increase their affinity for HER2 receptors. To this end, DARPin G3 was selected as a template, and six-point mutations comprising Q26E, I32V, T49A, L53H, K101R, and G124V were created on its structure. Furthermore, the 3D structures were formed through homology modeling and evaluated using molecular dynamic simulation. Then, both structures were docked to the HER2 receptor using the HADDOCK web tool, followed by 100 ns of molecular dynamics simulation for both DARPins / HER2 complexes.
FINDINGS/RESULTS: The theoretical result confirmed both structures' stability. Molecular dynamics simulations reveal that the applied mutations on DARPin EG3-2 significantly improve the receptor binding affinity of DARPin.
The computationally engineered DARPin EG3-2 in this study could provide a hit compound for the design of promising anticancer agents targeting HER2 receptors.
人表皮生长因子受体2（HER2）在约25%的乳腺癌患者中过度表达；因此，对其进行抑制是癌症治疗中的一个治疗靶点。
在本研究中，设计了两种新的锚蛋白重复序列设计蛋白（DARPins）变体，命名为EG3-1和EG3-2，以提高它们对HER2受体的亲和力。为此，选择DARPin G3作为模板，并在其结构上产生了包括Q26E、I32V、T49A、L53H、K101R和G124V的六点突变。此外，通过同源建模形成三维结构，并使用分子动力学模拟进行评估。然后，使用HADDOCK网络工具将这两种结构与HER2受体对接，随后对两种DARPins/HER2复合物进行100纳秒的分子动力学模拟。
理论结果证实了两种结构的稳定性。分子动力学模拟表明，在DARPin EG3-2上进行的突变显著提高了DARPin的受体结合亲和力。
本研究中通过计算工程设计的DARPin EG3-2可为设计有前景的靶向HER2受体的抗癌药物提供一种先导化合物。
