2. Academic Validation
  3. Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design

Structural insights into targeting of the colchicine binding site by ELR510444 and parbendazole to achieve rational drug design

  • RSC Adv. 2021 May 25;11(31):18938-18944. doi: 10.1039/d1ra01173a.
Jia-Hong Lei 1,  Ling-Ling Ma 2,  Jing-Hong Xian 3,  Hai Chen 2,  Jian-Jian Zhou 4,  Hao Chen 5,  Qian Lei 2,  Yu-Yan Li 1 2,  Yan-Yan Wang 6,  Yu-Xi Wang 1 2
Affiliations

Affiliations

  • 1 Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy Chengdu 610041 P. R. China [email protected].
  • 2 Targeted Tracer Research and Development Laboratory, Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University Chengdu 610041 P. R. China.
  • 3 Department of Clinical Research, West China Hospital Sichuan University Chengdu 610041 P. R. China.
  • 4 Beijing Loham Co.,Limited Beijing 100068 P. R. China.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center Memphis Tennessee 38163 USA.
  • 6 West China National Clinical Research Center for Geriatrics, School of Nursing, Sichuan University Chengdu 610041 P. R. China [email protected].
PMID: 35478655 DOI: 10.1039/d1ra01173a
Abstract

Microtubules consisting of α- and β-tubulin heterodimers have proven to be an efficient drug target for Cancer therapy. A broad range of agents, including ELR510444 and parbendazole, can bind to tubulin and interfere with microtubule assembly. ELR510444 and parbendazole are colchicine binding site inhibitors with antiproliferative activities. However, the lack of structural information on the tubulin-ELR510444/parbendazole complex has hindered the design and development of more potent drugs with similar scaffolds. Therefore, we report the crystal structures of tubulin complexed with ELR510444 at a resolution of 3.1 Å and with parbendazole at 2.4 Å. The structure of these complexes revealed the intermolecular interactions between the two colchicine binding site inhibitors and tubulin, thus providing a rationale for the development of novel benzsulfamide and benzimidazole derivatives targeting the colchicine binding site.

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