Small molecules found in natural products provide therapeutic benefits due to their pharmacological or biological activity, which may increase or decrease the expression of human epidermal growth factor receptor (HER), a promising target in the modification of signaling cascades involved in excessive cellular growth. In this study, in silico molecular protein-ligand docking protocols were performed with AutoDock Vina in order to evaluate the interaction of 800 natural compounds (NPs) from the

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... tProd Collection (http://www.msdiscovery.com/natprod.html), with four human HER family members: HER1 (PDB: 2ITW), HER2 (PDB: 3PP0), HER3 (PDB: 3LMG) and HER4 (PDB: 2R4B). The best binding affinity values (kcal/mol) for docking pairs were obtained for HER1-podototarin (−10.7), HER2-hecogenin acetate (−11.2), HER3-hesperidin (−11.5) and HER4-theaflavin (−10.7). The reliability of the theoretical calculations was evaluated employing published data on HER inhibition correlated with in silico binding calculations. IC 50 values followed a significant linear relationship with the theoretical binding Affinity data for HER1 (R = 0.656, p < 0.0001) and HER2 (R = 0.543, p < 0.0001), but not for HER4 (R = 0.364, p > 0.05). In short, this methodology allowed the identification of several NPs as HER inhibitors, being useful in the discovery and design of more potent and selective anticancer drugs. Molecules 2017, 22, 308 2 of 12 of these receptors have special characteristics, such as HER2 and HER3; HER2 possesses no known natural ligands [13, 14] and HER3, the only member of the HER family lacking intrinsic tyrosine kinase activity [15] . The activation of HER receptors is the result of their ability to bind effectively to different ligands, like epidermal growth factor (EGF), transforming growth factor-α (TGFA), heparin-binding EGF-like growth factor, amphiregulin, betacellulin, epiregulin and the latest addition to the mammalian family of EGFR, epigen [16] , either specifically or to one or more receptors. After ligand binding to the extracellular domain of the receptor, a conformational change takes place in form of functionally active dimers (EGFR-EGFR (homodimer) or EGFR-HER2, EGFR-HER3, EGFR-HER4 (heterodimer)). This allows the transphosphorylation on tyrosine residue to induce and enhance the activation of the intrinsic tyrosine kinase domain [3] , process that ultimately modifies the behavior of a normal cell through the output of signals for cellular proliferation, anti-apoptosis, angiogenesis and metastasis [17] . Given the prominent importance of EGFR signaling in cancer development, scientists have developed the following strategies: anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors (TKIs) [18] . Anti-EGFR antibodies, e.g., cetuximab and panitumumab, bind to the extracellular domain of EGFR monomer and compete against endogenous ligands by receptor binding, blocking ligand-induced receptor activation. Small molecule EGFR inhibitors, such as erlotinib, gefitinib and lapatinib, compete specifically with ATP for bind to the catalytic tyrosine kinase domain, inhibiting autophosphorylation processes and downstream signaling of cancer cells [18] . The inhibition of EGFR and its related proteins is considered as a standard approach in cancer investigations. Nevertheless, the existence of specific mutations in the receptor, restricts the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). These, can make more effective treatments as seen in the example of the rare I744M exon 19 mutation of EGFR, which could predict dramatic responsiveness to TKI [19]; or the presence of the T790M gatekeeper mutation, located in the EGFR tyrosine kinase domain, which accounts for half of drugs resistance [20] [21] [22] , posing a threat to the overall efficacy of this strategy. In order to surpass and address the obstacles that can lead to the resistance mechanisms there is a growing need to find and develop new generations of EGFR-TKIs with broad kinase selectivity and desirable physicochemical properties that can in one way or another intervene in the blockage of EGFR mediated oncogenic function. A well-known approach is the use of natural products in response to the unmet medical needs described above. In this work, we suggest the application of computational tools, including molecular docking methods, pharmacophores, and web server ADME/Tox property calculator for the identification of lead compounds from small sized natural compounds (NatProd Collection), as potential chemopreventive agents that can be key to the discovery and development of new therapeutic drug candidates by modulation of the kinase domain of the ErbB (HER) receptors. Results and Discussion Structural Comparison of HER Receptors The superposition of the 3D HER receptor structures (PDBs: 2ITW, 3PP0, 3LMG, 2R4B) as well as the RMSD values for each pair of them are presented in Figure 1 . The three-dimensional structures of HER receptors have some differences. The comparative structural analysis considered in this work for the four human HER receptors (whole proteins), showed a sequence identity in a range between 65.9% and 82.47%, indicating structural differences, that were also observed for their 3D structures, with RMSD values ranging between 3.0 and 5.7 Å (Figure 1 ), being HER1 (2ITW) the one with the greatest spatial differences in terms of backbone alpha carbons (4.2-5.7 Å), compared with the other HER structures. Sample Availability: Samples of the compounds are not available.