Virtual Screening Approaches in Identification of Bioactive Compounds Akin to Delphinidin as Potential HER2 Inhibitors for the Treatment of Breast Cancer

  • Patidar, Kavisha (In silico Research Laboratory, Eminent Biosciences, Devi Ahilya University) ;
  • Deshmukh, Aruna (In silico Research Laboratory, Eminent Biosciences, Devi Ahilya University) ;
  • Bandaru, Srinivas (Institute of Genetics and Hospital for Genetic Diseases, Osmania University) ;
  • Lakkaraju, Chandana (Institute of Genetics and Hospital for Genetic Diseases, Osmania University) ;
  • Girdhar, Amandeep (In silico Research Laboratory, Eminent Biosciences, Devi Ahilya University) ;
  • Gutlapalli, VR (In silico Research Laboratory, Eminent Biosciences, Devi Ahilya University) ;
  • Banerjee, Tushar (School of Life Science, Devi Ahilya University) ;
  • Nayarisseri, Anuraj (In silico Research Laboratory, Eminent Biosciences, Devi Ahilya University) ;
  • Singh, Sanjeev Kumar (Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University)
  • Published : 2016.06.01


Small molecule tyrosine kinase inhibitors targeting HER 2 receptors have emerged as an important therapeutic approach in inhibition of downstream proliferation and survival signals for the treatment of breast cancers. Recent drug discovery efforts have demonstrated that naturally occurring polyphenolic compounds like delphinidin have potential to inhibit proliferation and promote apoptosis of breast cancer cells by targeting HER2 receptors. While delphinidin may thus reduce tumour size, it is associated with serious side effects like dysphonia. Owing to the narrow therapeutic window of delphinidin, the present study aimed to identify high affinity compounds targeting HER2 with safer pharmacological profiles than delphinidin through virtual screening approaches. Delphinidin served as the query parent for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. The compounds retrieved were further subjected to Lipinski and Verber's filters to obtain drug like agents, then further filtered by diversity based screens with a cut off of 0.6. The compound with Pubchem ID: 91596862 was identified to have higher affinity than its parent. In addition it also proved to be non-toxic with a better ADMET profile and higher kinase activity. The compound identified in the study can be put to further in vitro drug testing to complement the present study.


  1. Babitha PP, Sahila MM, Srinivas Bandaru, et al (2015) Molecular docking and pharmacological investigations of rivastigminefluoxetine and coumarin–tacrine hybrids against acetyl choline esterase. Bioinformation, 11, 378-86.
  2. Bandaru S, Ponnala D, Lakkaraju C, et al (2014). Identification of high affinity non-peptidic small molecule inhibitors of MDM2-p53 interactions through structure-based virtual screening strategies. Asian Pac J Cancer Prev, 16, 3759-65.
  3. Chanda S, Anuradha N, Srinivas B, et al (2015). An in silico approach for identification of novel inhibitors as a potential therapeutics targeting hiv-1 viral infectivity factor. Curr Top Med Chem, 15, 65-72.
  4. Cheng F, Li W, Zhou Y, et al (2012). AdmetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model, 52, 3099-105.
  5. Desai SB, Moonim MT, Amarinder KG, et al (2000). Hormone receptor status of breast cancer in India: a study of 798 tumours. Breast, 9, 267-70.
  6. Dunna NR, Kandula V, Girdhar A, et al (2015). High Affinity Pharmacological Profiling Of Dual Inhibitors Targeting Ret And Vegfr2 In Inhibition Of Kinase And Angiogeneis Events In Medullary Thyroid Carcinoma. Asian Pac J Cancer Prev, 16, 7089-795.
  7. Franklin, MC, Carey KD, Vajdos FF, et al (2004). Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer cell, 5, 317-28.
  8. Gimanez MA, Drago SR, Bassett MN, et al (2016). Nutritional improvement of corn pasta-like product with broad bean (Vicia faba) and quinoa (Chenopodium quinoa). Food Chem, 199, 150-56.
  9. Hafeez BB, Siddiqui IA, Asim M et al (2008). A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer PC3 cells In vitro and in vivo: involvement of nuclear factor-${\kappa}B$ signaling. Cancer Res, 68, 8564-72.
  10. Jorgensen WL, Tirado-RJ (2005). Potential energy functions for atomic-level simulations of water and organic and biomolecular systems. Proc Natl Acad Sci U S A, 102, 6665-70.
  11. Kelotra S, Jain M, Kelotra A, et al (2014). An in silico appraisal to identify high affinity anti-apoptotic synthetic tetrapeptide inhibitors targeting the mammalian caspase 3 enzyme. Asian Pac J Cancer Prev, 15, 10137-42.
  12. Lipinski CA, et al (2004). Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol, 1, 337-41.
  13. Maunz A, Gütlein M, Rautenberg M, et al (2013). Lazar: a modular predictive toxicology framework. Front Pharmacol, 4, 38
  14. Nelder JA, Mead R (1965). A simplex method for function minimization. Comput J, 7, 308-13.
  15. Ozbay T, Nahta R (2011). Delphinidin inhibits HER2 and Erk1/2 signaling and suppresses growth of HER2-overexpressing and triple negative breast cancer cell lines. Breast Cancer (Auckl), 5, 143-54.
  16. Park Y, Hyun-Tae S, Hae HJ, et al (2015). Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer. Oncotarget, 6, 32027-38.
  17. Parkin DM, Bray F, Ferlay J, et al (2001). Estimating the world cancer burden: Globocan 2000. Int J Cancer, 94, 153-56.
  18. Sahila MM, Babitha PP, Srinivas Bandaru, et al (2015) Molecular docking based screening of GABA (A) receptor inhibitors from plant derivatives. Bioinformation, 11, 280-89.
  19. Thomsen R, Christensen MH (2006). MolDock: a new technique for high-accuracy molecular docking. J Med Chem, 49, 3315-21.
  20. Vaidyanathan K, Kumar P, Reddy CO, et al (2010). ErbB-2 expression and its association with other biological parameters of breast cancer among Indian women. Indian J Cancer, 47, 8-15.
  21. Veber DF, Johnson SR, Cheng HY, et al (2002). Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem, 45, 2615-23.
  22. Vogel CL, Cobleigh MA, Tripathy D, et al (2002). Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol, 20, 719-26.