Research Paper Volume 13, Issue 16 pp 20246—20257

Identification of effective natural PIK3CA H1047R inhibitors by computational study

Naimeng Liu1, , Xinhui Wang2, , Xuan Li3, , Xiaye Lv4, , Haoqun Xie5, , Zhen Guo5, , Jing Wang5, , Gaojing Dou1,5, , Ye Du1, , Dong Song1, ,

  • 1 Department of Breast Surgery, The First Hospital of Jilin University, Changchun, China
  • 2 Department of Oncology, First People’s Hospital of Xinxiang, Xinxiang, China
  • 3 Department of Obstetrics and Gynecology, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China
  • 4 Department of Hematology, Honghui Hospital, Xi’an Jiao Tong University, Xi’an, China
  • 5 Clinical College, Jilin University, Changchun, China

Received: May 20, 2021       Accepted: August 3, 2021       Published: August 20, 2021
How to Cite

Copyright: © 2021 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with a poor prognosis and a high recurrence rate. PIK3CA gene is frequently mutated in breast cancer, with PIK3CA H1047R as the hotspot mutation reported in TNBC. We used the ZINC database to screen natural compounds that could be structurally modified to develop drugs targeting the PIK3CA H1047R mutant protein in the PI3K pathway. The LibDock module showed that 2,749 compounds could strongly bind to the PIK3CA H1047R protein. Ultimately, the top 20 natural ligands with high LibDock scores were used for further analyses including assessment of ADME (absorption, distribution, metabolism, and excretion), toxicity, stability, and binding affinity. ZINC000004098448 and ZINC000014715656 were selected as the safest drug candidates with strong binding affinity to PIK3CA H1047R, no hepatotoxicity, less carcinogenicity, better plasma protein binding (PPB) properties, and enhanced intestinal permeability and absorption than the two reference drugs, PKI-402 and wortmannin. Moreover, their lower potential energies than those of PIK3CA H1047R confirmed the stability of the ligand-receptor complex under physiological conditions. ZINC000004098448 and ZINC000014715656 are thus safe and stable leads for designing drugs against PIK3CA H1047R as part of a targeted therapeutic approach for patients with TNBC.


TNBC: Triple-negative breast cancer; ADME: Absorption distribution metabolic excretion; ER: Estrogen receptor; PR: Progesterone receptor; HER2: Human epidermal growth factor receptor 2; PIK3: Phosphoinositide-3 kinase; TCGA: The Cancer Genome Atlas; COSMIC: The Catalogue of Somatic Mutations in Cancer; pCR: Pathologic complete response; BBB level: Blood brain barrier level; CYP2D6: Cytochrome P450 2D6 inhibition; PPB level: Plasma protein binding properties level; DTP: Developmental toxicity potential; NTP: National Toxicology Program dataset.