Structural and molecular insights from dual inhibitors of EGFR and VEGFR2 as a strategy to improve the efficacy of cancer therapy.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor 2 (VEGFR2) are known as valid targets for cancer therapy. Overexpression of EGFR induces uncontrolled cell proliferation and VEGF expression triggering angiogenesis via VEGFR2 signaling. On the other hand, VEGF expression independent of EGFR signaling is already known as one of the mechanisms of resistance to anti-EGFR therapy. Therefore, drugs that act as dual inhibitors of EGFR and VEGFR2 can be a solution to the problem of drug resistance and increase the effectiveness of therapy. In this review, we summarize the relationship between EGFR and VEGFR2 signal transduction in promoting cancer growth and how their kinase domain structures can affect the selectivity of an inhibitor as the basis for designing dual inhibitors. In addition, several recent studies on the development of dual EGFR and VEGFR2 inhibitors involving docking simulations were highlighted in this paper to provide some references such as pharmacophore features of inhibitors and key residues for further research, especially in computer-aided drug design.

Imidazole[1,5-a]pyridine derivatives as EGFR tyrosine kinase inhibitors unraveled by umbrella sampling and steered molecular dynamics simulations.

Although the use of the tyrosine kinase inhibitors (TKIs) has been proved that it can save live in a cancer treatment, the currently used drugs bring in many undesirable side-effects. Therefore, the search for new drugs and an evaluation of their efficiency are intensively carried out. Recently, a series of eighteen imidazole[1,5-a]pyridine derivatives were synthetized by us, and preliminary analyses pointed out their potential to be an important platform for pharmaceutical development owing to their promising actions as anticancer agents and enzyme (kinase, HIV-protease,…) inhibitors. In the present theoretical study, we further analyzed their efficiency in using a realistic scenario of computational drug design. Our protocol has been developed to not only observe the atomistic interaction between the EGFR protein and our 18 novel compounds using both umbrella sampling and steered molecular dynamics simulations, but also determine their absolute binding free energies. Calculated properties of the 18 novel compounds were in detail compared with those of two known drugs, erlotinib and osimertinib, currently used in cancer treatment. Inspiringly the simulation results promote three imidazole[1,5-a]pyridine derivatives as promising inhibitors into a further step of clinical trials.

SHP2-EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action.

SHP2 is a positive regulator of the EGFR-dependent Ras/MAPK pathway. It dephosphorylates a regulatory phosphorylation site in EGFR that serves as the binding site to RasGAP (RASA1 or p120RasGAP). RASA1 is activated by binding to the EGFR phosphate group. Active RASA1 deactivates Ras by hydrolyzing Ras-bound GTP to GDP. Thus, SHP2 dephosphorylation of EGFR effectively prevents RASA1-mediated deactivation of Ras, thereby stimulating proliferation. Despite knowledge of this vital regulation in cell life, mechanistic in-depth structural understanding of the involvement of SHP2, EGFR, and RASA1 in the Ras/MAPK pathway has largely remained elusive. Here we elucidate the interactions, the factors influencing EGFR's recruitment of RASA1, and SHP2's recognition of the substrate site in EGFR. We reveal that RASA1 specifically interacts with the DEpY992LIP motif in EGFR featuring a proline residue at the +3 position C-terminal to pY primarily through its nSH2 domain. This interaction is strengthened by the robust attraction of two acidic residues, E991 and D990, of EGFR to two basic residues in the BC-loop near the pY-binding pocket of RASA1's nSH2. In the stable precatalytic state of SHP2 with EGFR (DADEpY992LIPQ), the E-loop of SHP2's active site favors the interaction with the (-2)-position D990 and (-4)-position D988 N-terminal to pY992 in EGFR, while the pY-loop constrains the (+4)-position Q996 C-terminal to pY992. These specific interactions not only provide a structural basis for identifying negative regulatory sites in other RTKs but can inform selective, high-affinity active-site SHP2 inhibitors tailored for SHP2 mutants.

Computational Analysis of Activation of Dimerized Epidermal Growth Factor Receptor Kinase Using the String Method and Markov State Model.

Epidermal growth factor receptor (EGFR) activation is accompanied by dimerization. During the activation of the intracellular kinase domain, two EGFR kinases form an asymmetric dimer, and one side of the dimer (receiver) is activated. Using the string method and Markov state model (MSM), we performed a computational analysis of the structural changes in the activation of the EGFR dimer in this study. The string method reveals the minimum free-energy pathway (MFEP) from the inactive to active structure. The MSM was constructed from numerous trajectories of molecular dynamics simulations around the MFEP, which revealed the free-energy map of structural changes. In the activation of the receiver kinase, the unfolding of the activation loop (A-loop) is followed by the rearrangement of the C-helix, as observed in other kinases. However, unlike other kinases, the free-energy map of EGFR at the asymmetric dimer showed that the active state yielded the highest stability and revealed how interactions at the dimer interface induced receiver activation. As the H-helix of the activator approaches the C-helix of the receiver during activation, the A-loop unfolds. Subsequently, L782 of the receiver enters the pocket between the G- and H-helices of the activator, leading to a rearrangement of the hydrophobic residues around L782 of the receiver, which constitutes a structural rearrangement of the C-helix of the receiver from an outward to an inner position. The MSM analysis revealed long-time scale trajectories via kinetic Monte Carlo.

Targeting EGFR and VEGFR-2 Kinases With Nanoparticles: A Computational Approach for Cancer Therapy Advancement.

The study investigates titanium and zinc nanoparticles as inhibitors for the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), pivotal regulators of cell processes. VEGFR-2 activation fuels tumor angiogenesis in cancer cells, sustaining malignant tissue expansion. Molecular docking analysis illustrates the nanoparticles' binding to the active sites, inhibiting the phosphorylation of key proteins in downstream signaling. This inhibition offers a promising therapeutic approach to impede cancer-related signaling, potentially slowing down aberrant protein cascades controlled by EGFR and VEGFR-2. The findings propose a novel avenue for cancer treatment, targeting abnormal growth pathways using titanium and zinc nanoparticles.

RLP system: A single-tube two-step approach with dual amplification cascades for rapid identification of EGFR T790M.

BACKGROUND: The detection of cancer gene mutations in biofluids plays a pivotal role in revolutionizing disease diagnosis. The presence of a large background of wild-type sequences poses a challenge to liquid biopsy of tumor mutation genes. Suppressing the detection of wild-type sequences can reduce their interference, however, due to the minimal difference between mutant and wild-type sequences (such as single nucleotide variants differing by only one nucleotide), how to suppress the detection of wild-type sequences to the greatest extent without compromising the sensitivity of mutant sequence detection remains to be explored. SIGNIFICANCE: The RLP system addresses the incompatibility between RPA and RT-PCR reactions through a physical separation strategy. Besides, due to the remarkable flexibility of locked nucleic acid probes, the RLP system emerges as a potent tool for detecting mutations across diverse genes. It excels in sensitivity and speed, tolerates plasma matrix, and is cost-effective. This bodes well for advancing the field of precision medicine. RESULTS: The recombinase-assisted locked nucleic acid (LNA) probe-mediated dual amplification biosensing platform (namely RLP), which combines recombinase polymerase amplification (RPA) and LNA clamp PCR method in one tube, enabling highly sensitive and selective detection of EGFR T790M mutation under the help of well-designed LNA probes. This technique can quantify DNA targets with a limit of detection (LoD) at the single copy level and identify point mutation with mutant allelic fractions as low as 0.007 % in 45 min. Moreover, RLP has the potential for the direct detection of plasma samples without the need for nucleic acid extraction and the cost of a single test is less than 1USD. Furthermore, the RLP system is a cascading dual amplification reaction conducted in a single tube, which eliminates the risk of cross-contamination associated with opening multiple tubes and ensures the reliability of the results.

Allosteric inhibition of the epidermal growth factor receptor through disruption of transmembrane interactions.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) commonly targeted for inhibition by anticancer therapeutics. Current therapeutics target EGFR's kinase domain or extracellular region. However, these types of inhibitors are not specific for tumors over healthy tissue and therefore cause undesirable side effects. Our lab has recently developed a new strategy to regulate RTK activity by designing a peptide that specifically binds to the transmembrane (TM) region of the RTK to allosterically modify kinase activity. These peptides are acidity-responsive, allowing them to preferentially target acidic environments like tumors. We have applied this strategy to EGFR and created the PET1 peptide. We observed that PET1 behaves as a pH-responsive peptide that modulates the configuration of the EGFR TM through a direct interaction. Our data indicated that PET1 inhibits EGFR-mediated cell migration. Finally, we investigated the mechanism of inhibition through molecular dynamics simulations, which showed that PET1 sits between the two EGFR TM helices; this molecular mechanism was additionally supported by AlphaFold-Multimer predictions. We propose that the PET1-induced disruption of native TM interactions disturbs the conformation of the kinase domain in such a way that it inhibits EGFR's ability to send migratory cell signals. This study is a proof-of-concept that acidity-responsive membrane peptide ligands can be generally applied to RTKs. In addition, PET1 constitutes a viable approach to therapeutically target the TM of EGFR.

Multiple Mutations within Individual Oncogenes: Examples and Clinical Implications.

Gain-of-function mutations had been believed to function as a single mutation in oncogenes, although some secondary mutations, such as EGFR T790M mutations, are frequently acquired in patients that are resistant to tyrosine kinase inhibitor treatment. Recently, we and other investigators have reported that multiple mutations (MMs) frequently occur in the same oncogene before any therapy. In a recent pan-cancer study, we identified 14 pan-cancer oncogenes (such as PIK3CA and EGFR) and 6 cancer type-specific oncogenes that are significantly affected by MMs. Of these, 9% of cases with at least one mutation have MMs that are cis-presenting on the same allele. Interestingly, MMs show distinct mutational patterns in various oncogenes relative to single mutations in terms of mutation type, position, and amino acid substitution. Specifically, functionally weak, uncommon mutations are overrepresented in MMs, which enhance oncogenic activity in combination. Here, we present an overview of the current understanding of oncogenic MMs in human cancers and provide insights into their underlying mechanisms and clinical implications.

Peptide-functionalized therapeutic nanoplatform for treatment orthotopic triple negative breast cancer and bone metastasis.

Epidermal Growth Factor Receptor (EGFR) is a promising therapeutic target for triple-negative breast cancer (TNBC). Recently, specific EGFR-targeting peptide GE11-based delivery nano-system shows excellent potential because of its chemical versatility and good targeting ability. However, no further research focusing on the downstream of EGFR after binding with GE11 was explored. Hence, we tailor-designed a self-assembled nanoplatform named GENP using amphiphilic molecule of stearic acid-modified GE11. After loading doxorubicin (DOX), the resulted nanoplatform GENP@DOX demonstrated high loading efficiency and sustainable drug release. Importantly, our findings proved that GENP alone significantly suppressed the proliferation of MDA-MB-231 cells via EGFR-downstream PI3K/AKT signaling pathways, contributing to the synergistic treatment with its DOX release. Further work illustrated remarkable therapeutic efficacy both in orthotopic TNBC and its bone metastasis models with minimal biotoxicity. Together, the results highlight that our GENP-functionalized nanoplatform is a promising strategy for the synergistic therapeutic efficacy targeting EGFR-overexpressed cancer.

Coupled folding-upon-binding of human tumor suppressor MIG6 to lung cancer EGFR kinase domain and molecular trimming/stapling of MIG6-derived ß-hairpins to target the coupling event.

Human epidermal growth factor receptor (EGFR) is involved in strong association with malignant proliferation, which has been shown to play a central role in the development and progression of non-small cell lung cancer and other solid tumors. The tumor-suppressor protein MIG6 is a negative regulator of EGFR kinase activity by binding at the activation interface of asymmetric dimer of EGFR kinase domain to disrupt EGFR dimerization and then inactivate the kinase. The protein adopts two discrete fragments 1 and 2 to directly interact with EGFR. It is revealed that the MIG6 fragment 2 is intrinsically disordered in free unbound state, but would fold into a well-structured ß-hairpin when binding to EGFR, thus characterized by a so-called coupled folding-upon-binding process, which can be regarded as a compromise between favorable direct readout and unfavorable indirect readout. Here, a 23-mer F2P peptide was derived from MIG6 fragment 2, trimmed into a 17-mer tF2P peptide that contains the binding hotspot region of the fragment 2, and then constrained with an ordered hairpin conformation in free unbound state by disulfide stapling, finally resulting in a rationally stapled/trimmed stF2P peptide that largely minimizes the unfavorable indirect readout effect upon its binding to EGFR kinase domain, with affinity improved considerably upon the trimming and stapling/trimming. These rationally designed ß-hairpin peptides may be further exploited as potent anti-lung cancer agents to target the activation event of EGFR dimerization.

Regulation of Signaling from the Epidermal Growth Factor Family.

The epidermal growth factor (EGF) system has allowed chemists, biologists, and clinicians to improve our understanding of cell production and cancer therapy. The discovery of EGF led to the recognition of cell surface receptors capable of controlling the proliferation and survival of cells. The detailed structures of the EGF-like ligand and the responses of their receptors (EGFR-family) has revealed the conformational and aggregation changes whereby ligands activate the intracellular kinase domains. Biophysical analysis has revealed the preformed clustering of different EGFR-family members and the processes which occur on ligand binding. Understanding these receptor activation processes and the consequential cytoplasmic signaling has allowed the development of inhibitors which are revolutionizing cancer therapy. This Review describes the recent progress in our understanding of the activation of the EGFR-family, the effects of signaling from the EGFR-family on cell proliferation, and the targeting of the EGFR-family in cancer treatment.

In Silico Prospects and Therapeutic Applications of Ouabagenin and Hydroxylated Corticosteroid Analogues in the Treatment of Lung Cancer.

Lung cancer is the second most prevalent carcinoma around the world, and about 80% of patients are of non-small cell lung cancer (NS-CLC). Epidermal growth factor receptor (EGFR) is the most expressed protein kinases in lung cancer and hence can be used in target-related anti-cancer therapy. Here, computational approach is used for the exploration of the anti-cancer potential of new steroid derivatives as previously no in vitro data was available for them. Initially, DFT calculations of all compounds were determined to analyze the electronic density of optimized structures. The HOMO and LUMO orbital analysis of all derivatives was analyzed, to investigate the reactivity of compounds. Afterwards, optimized structures were used for molecular docking studies in which all ouabagenin derivatives were docked within the EGFR active site using MOE software. Moreover, anti-cancer potential of selected derivatives was evaluated on the basis of binding interactions with three anti-cancer proteins. The binding scores of these compounds were compared with the FDA-approved drug, i.e., gefitinib. The findings of current study suggested that selected derivatives exhibited significant inhibiting potential of anti-cancer proteins and EGFR. Particularly, compound OD3 is the potent inhibitor of anti-cancer and EGFR protein with the highest binding energies. These novel steroidal derivatives are subjected to in silico analysis for the first time against lung cancer. These compounds possess potential anti-cancerous properties and can be explored further for in vitro and in vivo studies.

Allele-specific activation, enzyme kinetics, and inhibitor sensitivities of EGFR exon 19 deletion mutations in lung cancer.

Oncogenic mutations within the epidermal growth factor receptor (EGFR) are found in 15 to 30% of all non-small-cell lung carcinomas. The term exon 19 deletion (ex19del) is collectively used to refer to more than 20 distinct genomic alterations within exon 19 that comprise the most common EGFR mutation subtype in lung cancer. Despite this heterogeneity, clinical treatment decisions are made irrespective of which EGFR ex19del variant is present within the tumor, and there is a paucity of information regarding how individual ex19del variants influence protein structure and function. Herein, we identified allele-specific functional differences among ex19del variants attributable to recurring sequence and structure motifs. We built all-atom structural models of 60 ex19del variants identified in patients and combined molecular dynamics simulations with biochemical and biophysical experiments to analyze three ex19del mutations (E746_A750, E746_S752 > V, and L747_A750 > P). We demonstrate that sequence variation in ex19del alters oncogenic cell growth, dimerization propensity, enzyme kinetics, and tyrosine kinase inhibitor (TKI) sensitivity. We show that in contrast to E746_A750 and E746_S752 > V, the L747_A750 > P variant forms highly active ligand-independent dimers. Enzyme kinetic analysis and TKI inhibition experiments suggest that E746_S752 > V and L747_A750 > P display reduced TKI sensitivity due to decreased adenosine 5'-triphosphate Km. Through these analyses, we propose an expanded framework for interpreting ex19del variants and considerations for therapeutic intervention.

Novel Antibody-Peptide Binding Assay Indicates Presence of Immunoglobulins against EGFR Phospho-Site S1166 in High-Grade Glioma.

We investigated the feasibility of detecting the presence of specific autoantibodies against potential tumor-associated peptide antigens by enriching these antibody-peptide complexes using Melon Gel resin and mass spectrometry. Our goal was to find tumor-associated phospho-sites that trigger immunoreactions and raise autoantibodies that are detectable in plasma of glioma patients. Such immunoglobulins can potentially be used as targets in immunotherapy. To that aim, we describe a method to detect the presence of antibodies in biological samples that are specific to selected clinically relevant peptides. The method is based on the formation of antibody-peptide complexes by mixing patient plasma with a glioblastoma multiforme (GBM) derived peptide library, enrichment of antibodies and antibody-peptide complexes, the separation of peptides after they are released from immunoglobulins by molecular weight filtration and finally mass spectrometric quantification of these peptides. As proof of concept, we successfully applied the method to dinitrophenyl (DNP)-labeled α-casein peptides mixed with anti-DNP. Further, we incubated human plasma with a phospho-peptide library and conducted targeted analysis on EGFR and GFAP phospho-peptides. As a result, immunoaffinity against phospho-peptide GSHQIS[+80]LDNPDYQQDFFPK (EGFR phospho-site S1166) was detected in high-grade glioma (HGG) patient plasma but not in healthy donor plasma. For the GFAP phospho-sites selected, such immunoaffinity was not observed.

Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors.

Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug's ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.

Studies on ligand-based pharmacophore modeling approach in identifying potent future EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is a validated drug target for cancer chemotherapy. Mutations in EGFR are directly linked with the development of drug resistance and this has led for the development of newer drugs in quest for more efficacious inhibitors. The current research is focused on identifying potential and safe molecules as EGFR inhibitors by using both structure and ligand based computational approaches. In quest for finding newer moieties, we have developed a pharmacophore model utilizing drugs like lazertinib, osimertinib, nazartinib, avitinib, afatininb, and talazoparib that are known to inhibit EGFR along with their downstream signaling. Ligand-based pharmacophore model have been developed to screen the ZINC database through ZINCPharmer webserver. The server has identified 9482 best possible ligands with high pharmacophoric similarity i.e., RMSD value less than 0.2 Å. The top 10 ligands with the criteria of dock score(s) and interactions were further subjected to in silico ADMET studies giving two plausible ligands that were further subjected to Molecular Dynamics and MM/PBSA free energy calculations to ensure stability to the target site. Results deduced by in silico work in the current study may be corroborated biologically in the future. The current work, therefore, provides ample opportunity for computational and medicinal chemists to work in allied areas to facilitate the design and development of novel and more efficacious EGFR inhibitors for future experimental studies.

Analysis of changes of cavity volumes in predefined directions of protein motions and cavity flexibility.

Dynamics of protein cavities associated with protein fluctuations and conformational plasticity is essential for their biological function. NMR ensembles, molecular dynamics (MD) simulations, and normal mode analysis (NMA) provide appropriate frameworks to explore functionally relevant protein dynamics and cavity changes relationships. Within this context, we have recently developed analysis of null areas (ANA), an efficient method to calculate cavity volumes. ANA is based on a combination of algorithms that guarantees its robustness against numerical differentiations. This is a unique feature with respect to other methods. Herein, we present an updated and improved version that expands it use to quantify changes in cavity features, like volume and flexibility, due to protein structural distortions performed on predefined biologically relevant directions, for example, directions of largest contribution to protein fluctuations (principal component analysis [PCA modes]) obtained by MD simulations or ensembles of NMR structures, collective NMA modes or any other direction of motion associated with specific conformational changes. A web page has been developed where its facilities are explained in detail. First, we show that ANA can be useful to explore gradual changes of cavity volume and flexibility associated with protein ligand binding. Secondly, we perform a comparison study of the extent of variability between protein backbone structural distortions, and changes in cavity volumes and flexibilities evaluated for an ensemble of NMR active and inactive conformers of the epidermal growth factor receptor structures. Finally, we compare changes in size and flexibility between sets of NMR structures for different homologous chains of dynein.

Theoretical evaluation of EGFR kinase inhibition and toxicity of di-indol-3-yl disulphides with anti-cancer potency.

Research aimed at developing potent di-indol-3-yl disulphides for cancer diseases makes use of various theoretical techniques to evaluate the drug-likeness parameters and the mode of action. A drug-likeness filter helps evaluate the therapeutic potency of four bis-indole derivatives, structurally related to 3,3'-methanediyl-bis-indole (DIM) but having the S-S instead of the methylene linker and showing a high inhibitory impact on the variants of cancer cell lines (among them HL-60 and DU-145). Based on in vitro experimental results for their close analogues, a correlation was found between the epidermal growth factor receptor kinase (EGFR) inhibition and the theoretical energy of complexation. Docking studies of ligands followed by molecular dynamics were performed at the ATP-binding site of EGFR tyrosine kinase to scrutinize the inhibition of the di-indol-3-yl disulphides at a molecular level. Derivatives with bromine or iodine substituents at C-5 positions of the indole moieties made strong complexes by interaction with the most important hinge region residues Met-793 and Cys-733. The inhibition model for EGFR kinase and the proposed procedures can be very informative in the biological testing of selected bis-indoles and may be useful for future research on effective inhibitors for the treatment of EGFR-related cancer.Communicated by Ramaswamy H. Sarma.

Molecular docking and dynamic simulation to identify potential phytocompound inhibitors for EGFR and HER2 as anti-breast cancer agents.

Breast cancer is the most prevalent cancer in women worldwide. To treat human breast cancer by inhibiting EGFR and HER2 targets is an important therapeutic option. Phytochemicals are found to have beneficial health effects in treating various diseases. An effort has been made to virtually screen phytochemical inhibitor by molecular docking and dynamic simulation in the current studies. The docking scores analysis resulted in a common hit Panaxadiol ligand with a low dock score for EGFR and HER2 targets. The inhibitory action of the phytocompounds was also validated by comparing it with the reference compounds Erlotinib for EGFR and Neratinib for HER2. Molecular dynamic simulation of EGFR and HER2 lead complexes ensure the ligand's appropriate refinement in the dynamic system. The target and ligand complex interaction motif established a high affinity of lead candidates in a dynamic system similar to molecular docking results. This study reveals that Panaxadiol hit molecule can be developed as a novel multi-target EGFR and HER2 target inhibitor with greater potential and low toxicity.Communicated by Ramaswamy H. Sarma.

Molecular docking and molecular dynamic studies: screening of phytochemicals against EGFR, HER2, estrogen and NF-KB receptors for their potential use in breast cancer.

Breast cancer (BC) is a second common malignancy in female globally. Hence, identification of novel therapeutic agents is extremely important. Molecular docking and MD simulation are the important tools in the process of drug discovery for searching the potential hits. The structure-based drug designing technique also reveals the information about ligands behavior in computational environment. Docking tools help in visualization and analysis of protein-ligand complex at atomic level. Molecular dynamics shows the stability of the molecules in the receptor cavity in the simulated environment. In this research work, we have screened potent phytochemicals against the BC. We docked the phytochemicals and examined the binding affinities of ligands towards the EGFR, HER2, estrogen and NF-κB receptors. Pristimerin, ixocarpalactone A, viscosalactone B and zhankuic acid A have shown higher binding affinities and energies towards targeted receptors among the screened phytochemicals. MD simulation study shows stability of docked complex for pristimerin and HER2 receptor. These phytochemicals can be repurposed for their anticancer activity. This in-silico work provides a strong ground for further investigation of their anticancer activity.