Ligand Binding Interactions Research Articles

Machine Learning Approaches for Metalloproteins.

Metalloproteins are a family of proteins characterized by metal ion binding, whereby the presence of these ions confers key catalytic and ligand-binding properties. Due to their ubiquity among biological systems, researchers have made immense efforts to predict the structural and functional roles of metalloproteins. Ultimately, having a comprehensive understanding of metalloproteins will lead to tangible applications, such as designing potent inhibitors in drug discovery. Recently, there has been an acceleration in the number of studies applying machine learning to predict metalloprotein properties, primarily driven by the advent of more sophisticated machine learning algorithms. This review covers how machine learning tools have consolidated and expanded our comprehension of various aspects of metalloproteins (structure, function, stability, ligand-binding interactions, and inhibitors). Future avenues of exploration are also discussed.

Preparation and Evaluation of Chitosan/PVA Based Hydrogel Films Loaded with Honey for Wound Healing Application

In the present study, chitosan/polyvinyl alcohol (PVA)-based honey hydrogel films were developed for potential wound healing application. The hydrogel films were developed by a solvent-casting method and were evaluated in terms of thickness, weight variation, folding endurance, moisture content and moisture uptake. The water vapor transmission rate was found to range between 1650.50 ± 35.86 and 2698.65 ± 76.29 g/m2/day. The tensile strength and elongation at break were found to range between 4.74 ± 0.83 and 38.36 ± 5.39 N, and 30.58 ± 3.64 and 33.51 ± 2.47 mm, respectively, indicating significant mechanical properties of the films. SEM images indicated smooth surface morphology of the films. FTIR, DSC and in silico analysis were performed, which highlighted the docking energies of the protein–ligand complex and binding interactions such as hydrogen bonding, Pi–Pi bonding, and Pi–H bonding between the selected compounds and target proteins; hence, we concluded, with the three best molecules (lumichrome, galagin and chitosan), that there was wound healing potential. In vitro studies pointed toward a sustained release of honey from the films. The antimicrobial performance of the films was investigated against Staphylococcus aureus. Overall, the results signaled the potential application of chitosan/PVA based hydrogel films as wound dressings. Furthermore, in vivo experiments may be required to evaluate the clinical efficacy of honey-loaded chitosan/PVA hydrogel films in wound healing.

Unraveling the Role of π-Stacking Interactions in Ligand Binding to the Thiamine Pyrophosphate Riboswitch with High-level Quantum Chemical Calculations and Docking Study.

The thiamine pyrophosphate (TPP) riboswitch has emerged as the new target for designing new ligands for antibiotic purpose. Binding of the natural ligand TPP to the TPP riboswitch causes downregulation of the genes responsible for its biosynthesis. We have reported the role of π-stacking energy contributions to ligand binding with a TPP riboswitch. In conjunction with the docking study, the higher-level quantum chemical calculations performed with the wB97XD and Def2TZVPP basis set in the aqueous phase revealed that the optimum ring size is crucial to attain the effective binding efficiency of ligands with a TPP riboswitch. The π-stacking energy contributions observed for the ligands studied are largely similar; however, the cases studied with higher π-stacking energies with larger rings have a weaker ability to displace the radiolabeled thiamine from the riboswitch. The EDA and NCI analyses suggest the role of larger dispersive interactions in stabilizing the π-stacking rings. The contribution from hydrogen-bonding interactions of the hydrogen-bond donor groups on the A ring augments the binding affinity of the ligand. This study sheds light on various factors that contribute to the design of new ligands for efficient binding with a TPP riboswitch and inhibition of gene expression.

Methimazole Analogs as Urease Inhibitors: Synthesis, In Silico and In Vitro Evaluation

AbstractUrease plays a key role in urinary tract and gastrointestinal infections for which inhibition of it could prove to be substantial as a potential therapeutic option. Here, synthesized thirty novel compounds in four different series based on methimazole skeleton, also known as thiamazole, a drug that is used for the treatment of hyperthyroidism. Characterization of novel compounds consisting oxadiazoles, hydrazine‐1‐carbothioamides and N′‐arylidenebenzohydrazides were performed by 1H‐, 13C‐NMR and high resolution mass spectrometry (HRMS). The synthesized molecules were examined for structure‐activity relationship in urease inhibition and found to exhibit inhibitory potency in a range of IC50=3.56–14.08 μM compared to urea and acetohydroxamic acid used as standard. Moreover, molecular docking was performed to understand ligand binding interactions in the active site of the enzyme (Jack bean urease, Protein Data Bank ID 3LA4). The promise of addressing urinary tract and gastrointestinal disorders through urease inhibition is discussed.

P019 GS-1069518 is a potent and selective small molecule α4β7 inhibitor

Abstract Background The interaction between the adhesion molecule MAdCAM-1 and the α4β7 integrin heterodimer enables the trafficking of gut-antigen specific lymphocytes to the small and large intestines and to gut-associated lymphoid tissues. The role of the α4β7 integrin in the pathophysiology of IBD has been clinically demonstrated, and targeted therapeutics have been shown to mitigate inflammation and mucosal damage mediated by α4β7+ lymphocytes. The purpose of this study was to determine the potency and selectivity of the small molecule α4β7 inhibitor GS-1069518. Methods The selectivity of GS-1069518 and relevant reference molecules was determined using in vitro cell capture assays with natural integrin ligands and by measuring receptor occupancy in human and cynomolgus monkey whole blood. The number of RPMI-8866 cells binding to MAdCAM-1-coated surfaces (a natural α4β7 ligand) and Jurkat cells binding to VCAM-1-coated surfaces (a natural α4β1 ligand) were quantified with high content imaging. Receptor occupancy on CD3+CD4+CD45RO+β7+ (human) or CD3+CD4+CD45RA-β7+ (cynomolgus monkey) and CD3+CD4+CD45RO+α4+β1+β7- (human) or CD3+CD4+CD45RA-α4+β1+β7- (cynomolgus monkey) memory T cells was measured by flow cytometry with fluorescent probes that detect occupancy in the ligand-binding sites. Results In a MAdCAM-1 cell capture assay, the EC50 of GS-1069518 was 0.034 nM, with 71-fold and >10,000-fold selectivity over α4β1 and αLβ2, respectively. In α4β7 receptor occupancy assays the EC50 of GS-1069518 was 0.36 nM in human whole blood and 0.4 nM in cynomolgus monkey whole blood. GS-1069518 was 482-fold selective for α4β7 over α4β1 in human whole blood and 119-fold selective for α4β7 in cynomolgus monkey blood. Conclusion GS-1069518 is a highly potent and selective small molecule inhibitor of the α4β7-MAdCAM-1 ligand binding interaction.

Targeting Natural Polymeric DNAs with Harmane: An Insight into Binding and Thermodynamic Interaction Through Biophysical Approach.

DNA is one of the major molecular targets for a broad range of anticancer drugs. Hence, interaction studies involving cellular DNA and small molecules can be highly beneficial as they often lead to rational and efficient drug design. In this study, the binding interaction of Harmane (a naturally occurring, bioactive indole alkaloid) with two natural polymeric DNAs, that is, Calf thymus (CT) DNA and Herring testis (HT) DNA has been elucidated using biophysical techniques. A ground state, 1:1 complexation, was revealed by steady-state fluorescence spectroscopy. The thermodynamic profile and energetics of the associated reaction were evaluated by temperature-dependent fluorescence spectroscopy. The spontaneity of the binding was confirmed by the negative ΔG° values in both cases. Negative enthalpy change, along with stronger positive entropic contribution, indicated the dominant electrostatic nature of the interaction and finally the entropy-driven exothermic binding process throughout. Salt-dependent studies further demonstrated the significant contribution of electrostatic interactions in ligand binding toward DNA. Infrared data substantiated the structural information of the said interactions, leading to the exploration of the structure-function relationship.

New ON Schiff bases and their homoleptic Zn, Ni, and Cu complexes - Synthesis, structural characterization and DNA binding studies

New Schiff base ligands (L1H, L2H and L3H) and their homoleptic Zn(II) (1, 2 and 3), Ni(II) (4, 5 and 6), and Cu(II) (7, 8 and 9) complexes have been synthesized. The ligands were obtained by the reaction of 2-(3,4-dimethoxyphenyl)ethanamine with 5-chlorosalicylaldehyde, 5-bromosalicylaldehyde and 3-methoxysalicylaldehyde respectively. All these compounds were characterized by CHN analysis, FT-IR and UV–Vis spectroscopy. The structures of ligands and zinc complexes were also confirmed by 1H and 13C{1H} NMR spectroscopy. The molecular structures of L1H, L2H and 6 were determined by single crystal X-ray diffraction studies. In all complexes the monobasic ligands (L1, L2 and L3) act as ON donors by coordinate through azomethine nitrogen and phenolate oxygen to form complexes of composition [M(L1–3)2] (1–9). The crystal structures of L1H, L2H and 6 features CH…π and CH…O types of intermolecular secondary bonding interactions. The calf thymus-DNA binding interaction of ligands and complexes have been assessed by electronic absorption titrations which showed avid binding through intercalative mode and the binding constant (Kb) found in the order of 107M−1.

Virtual screening and molecular dynamic simulations of the antimalarial derivatives of 2-anilino 4-amino substituted quinazolines docked against a Pf-DHODH protein target

BackgroundThe processes of drug development and validation are too expensive to be subjected to experimental trial and errors. Hence, the use of the insilico approach becomes imperative. To this effect, the drug-likeness and pharmacokinetic properties of the ten (10) previously designed derivatives of 2-anilino 4-amino substituted quinazolines were carried out. Their predicted ligand binding interactions were also carried out by docking them against the Plasmodium falciparum dihydroorotate dehydrogenase (Pf-DHODH) protein target, and the stability of the complex was determined through dynamic simulations. The drug-likeness and pharmacokinetic characteristics were estimated using the online SwissADME software, while the Molegro Virtual Docker (MVD) software was used for molecular docking. And the dynamic simulation was performed for the duration of 100 ns to verify the stability of the docked complex, with the aid of a Schrödinger program, Desmond.ResultsThe designed derivatives were all found to pass the Lipinski test of drug likeness, while the pharmacokinetic studies result that the skin permeability and molar refractivity values of the derivatives are both within the limits. In addition, except for derivative C-01, most of the derivatives have strong gastrointestinal absorptions and lack Pgp substrate. Furthermore, no derivative inhibited CYP1A2, CYP2C9, or CYP2C19. The docking studies show the better binding affinities between the ligands and Pf-DHODH than those between the atovaquone or chloroquine standards. The derivative C-02, {5-((6,7-dimethoxy-4-((3-nitrobenzyl)amino)quinazolin-2-yl)amino)-2-fluorobenzaldehyde} was found to be the most stable derivative, with a re-rank docking score of − 173.528 kcal/mol and interaction energy of − 225.112 kcal/mol. The dynamic simulation analysis shows that the derivative C-02 forms a stable complex with the protein target over the simulation time.ConclusionsThe ability of these ligands to form hydrogen bonds, as well as various other interactions, was cited as a factor responsible for their better binding affinity. These findings could aid further the development of enhanced antimalarial drugs.

Characterization of protein-ligand binding interactions of enoyl-ACP reductase (FabI) by native MS reveals allosteric effects of coenzymes and the inhibitor triclosan.

The enzyme enoyl-ACP reductase (also called FabI in bacteria) is an essential member of the fatty acid synthase II pathway in plants and bacteria. This enzyme is the target of the antibacterial drug triclosan and has been the subject of extensive studies for the past 20 years. Despite the large number of reports describing the biochemistry of this enzyme, there have been no studies that provided direct observation of the protein and its various ligands. Here we describe the use of native MS to characterize the protein-ligand interactions of FabI with its coenzymes NAD+ and NADH and with the inhibitor triclosan. Measurements of the gas-phase affinities of the enzyme for these ligands yielded values that are in close agreement with solution-phase affinity measurements. Additionally, FabI is a homotetramer and we were able to measure the affinity of each subunit for each coenzyme, which revealed that both coenzymes exhibit a positive homotropic allosteric effect. An allosteric effect was also observed in association with the inhibitor triclosan. These observations provide new insights into this well-studied enzyme and suggest that there may still be gaps in the existing mechanistic models that explain FabI inhibition.

Probing Allosteric Modulation of Membrane Receptor in the Native State by Data Mining-Integrated Tracking Microscopy

Probing Allosteric Modulation of Membrane Receptor in the Native State by Data Mining-Integrated Tracking Microscopy

Structural and functional insight into thiazolidinone derivatives as novel candidates for anticancer drug design: in vitro biological and in-silico strategies

The compounds 2a–2h containing a thiazolidinone pharmacophore were synthesized via hetrerocylization of thiosemicarbazones with dimethyl acetylenedicarboxylate. The hybrid molecules were evaluated for anticancer activity against the human cell lines MCF-7, T47D (human breast adenocarcinoma) and HeLa (cervical cancer). Compounds 2c showed effective cytotoxicity on MCF-7 and HeLa (GI50 6.40 ± 0.10 μM/mL and GI5010.30 ± 1.09 μM/mL), and compound 2d also showed effective cytotoxicity against MCF-7 and HeLa cell lines i.e., (GI50 16.60 ± 0.21 μM/mL and GI50 15.02 ± 0.14 μM/mL). These findings were comparable to cisplatin (azane;dichloroplatinum) the standard drug (GI50 13.20 ± μM/mL and 15.10 μM/mL respectively) and consequently nominated for determination of the mode of cell death. The results revealed the cytotoxic effects of 2c and 2d by induction of apoptosis in MCF-7 and HeLa cell lines. Moreover the results were further supported by the Molecular Docking which predicts the binding interactions of the best anticancer ligands with Ribonucleotide reductase (RNR), which is essential enzyme required for de-novo synthesis of DNA precursors. Molecular dynamic simulations were also performed to determine the stability of protein-ligand complex under different simulated conditions. In addition, the computational studies including DFTs, ADMET properties suggested these compounds can act as lead molecules, for the synthesis of novel drug candidates for the treatment of specific cancer and its associated malignancies.

Berberine attenuates experimental autoimmune myasthenia gravis via rebalancing the T cell subsets

Myasthenia Gravis (MG) is a T cell-driven, autoantibody-mediated disease. Here we show that oral Berberine (BBR) ameliorated clinical symptoms of experimental autoimmune myasthenia gravis(EAMG) rat model via decreasing the frequencies of Th1, Th17, Th1/17 cell subsets. JAK-STAT pathway was highlighted by transcriptomic analysis with EAMG mononuclear cells (MNCs). Surface plasmon resonance identified ligand binding interaction between BBR and JAK2, and electrostatic interaction was proposed by molecular dynamic simulation. Reduced phosphorylated JAK1/2/3 and STAT1/3 in MNCs from BBR-fed EAMG rats were demonstrated. These results suggest that BBR might improve EAMG by rebalancing T cell subsets through targeting JAK-STAT pathway.

In silico studies of bacterial derived fatty acid as a potential inhibitor of 1FGE and 1BQO

Thrombomodulin (TM) and matrix metalloproteinase (MMPs) are the major factors that are responsible for lung cancer. Hence, the identification of novel compounds inhibiting TM and MMPs is the challenging task for the scientists. Even though synthetic drugs were developed, their toxicity and offtarget limit their usage. The current study aims to investigate the molecular simulations for bacterial derived stearic acid to estimate the in silico anticancer activity against TM and MMPs protein as target compounds and the findings were correlated with the standard drug vorinostat. Using Lamarckian genetic algorithm, the TM and MMPs were energy minimized and docked with stearic acid and vorinostat using auto dock 4.2 and visualized in PyMol software. Protein and ligand binding analysis revealed that stearic acid interacts with the amino acids of MMPs residues of PHE83, SER212, ALA213 and ASN214. It interacts with the TMs with two amino acid residues i.e. CYS407 and GLU408. Hence, compared to vorinostat, stearic acid shows a higher binding affinity towards MMPs and slightly lower affinity towards TM proteinase. We conclude that the computational analysis of ligand binding interaction of stearic acid suggests that it could be a potential inhibitor of matrix metallo proteinase and is effective against thrombomodulin and can be considered as an anticancer agent by in vivo studies.

Extracting Dynamical Correlations and Identifying Key Residues for Allosteric Communication in Proteins by correlationplus.

Extracting dynamical pairwise correlations and identifying key residues from large molecular dynamics trajectories or normal-mode analysis of coarse-grained models are important for explaining various processes like ligand binding, mutational effects, and long-distance interactions. Efficient and flexible tools to perform this task can provide new insights about residues involved in allosteric regulation and protein function. In addition, combining and comparing dynamical coupling information with sequence coevolution data can help to understand better protein function. To this aim, we developed a Python package called correlationplus to calculate, visualize, and analyze pairwise correlations. In this way, the package aids to identify key residues and interactions in proteins. The source code of correlationplus is available under LGPL version 3 at https://github.com/tekpinar/correlationplus. The current version of the package (0.2.0) can be installed with common installation methods like conda or pip in addition to source code installation. Moreover, docker images are also available for usage of the code without installation.

Design, synthesis and biological evaluation of cinnamamide-quinazoline derivatives as potential EGFR inhibitors to reverse T790M mutation

Gatekeeper T790M mutation in EGFR is the most common factor for acquired resistance. Acrylamide-bearing 4-anilinoquinazoline scaffold are powerful irreversible inhibitors for overcoming resistance. In this work, three series of EGFR inhibitors derived from incorporation of cinnamamide into the quinazoline scaffold were designed and synthesized to reverse resistance resulting from insurgence of T790M mutation. SAR studies revealed that methoxy and acetoxy substitutions on the cinnamic phenyl ring were found to elevate the activity. In particular, compound 7g emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib (0.95 μM) towards H1975 cells with an IC50 value of 1.22 μM. Kinase inhibition studies indicated that 7g showed excellent inhibitory effect on EGFRT790M enzyme, which was 11 times more effective than gefitinib. Besides, selectivity index of 7g toward the EGFRT790M mutant over the EGFRWT is 2.72, hinting its effect of reducing off-target. Mechanism study indicated that 7g induced apoptosis of H1975 cells and arrest the cell cycle at G2/M phase in a dose-dependent manner. Moreover, 7g could significantly inhibit the expression of p-EGFR and its downstream p-AKT and p-ERK in H1975 cells. Molecular docking was also performed to gain insights into the ligand-binding interactions of 7g inside EGFRWT and EGFRT790M binding sites.

Phylogenetic analyses, protein modeling and active site prediction of two pathogenesis related (PR2 and PR3) genes from bread wheat.

Wheat is a major staple food and has been extensively grown around the globe. Sessile nature of plants has exposed them to a lot of biotic and abiotic stresses including fungal pathogen attack. Puccinia graminis f.sp. tritici causes stem rust in the wheat crop and leads to 70% decrease in its production. Pathogenesis-related (PR) proteins provide plants with defense against different fungal pathogens as these proteins have antifungal activities. This study was designed to screen Pakistani wheat varieties for PR2 and PR3 proteins and their in silico characterization. PR2 and PR3 genes were screened and isolated by PCR amplification from wheat variety Chenab-70 and Frontana, respectively. The nucleotide sequences of PR2 and PR3 genes were deposited in GenBank with accession numbers MT303867 and MZ766118, respectively. Physicochemical properties, secondary and tertiary structure predictions, and molecular docking of protein sequences of PR2 and PR3 were performed using different bioinformatics tools and software. PR2 and PR3 genes were identified to encode β–1,3–glucanase and chitinase proteins, respectively. Molecular docking of both PR2 and PR3 proteins with beta-glucan and chitin (i.e. their respective ligands) showed crucial amino acid residues involved in molecular interactions. Conclusively, molecular docking analysis of β–1,3–glucanase and chitinase proteins revealed crucial amino acid residues which are involved in ligand binding and important interactions which might have important role in plant defense against fungal pathogens. Moreover, the active residues in the active sties of these proteins can be identified through mutational studies and resulting information might help understanding how these proteins are involved in plant defense mechanisms.

Anthraquinolone and quinolizine derivatives as an alley of future treatment for COVID-19: an in silico machine learning hypothesis

Coronavirus disease 2019 (Covid-19), caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has come to the fore in Wuhan, China in December 2019 and has been spreading expeditiously all over the world due to its high transmissibility and pathogenicity. From the outbreak of COVID-19, many efforts are being made to find a way to fight this pandemic. More than 300 clinical trials are ongoing to investigate the potential therapeutic option for preventing/treating COVID-19. Considering the critical role of SARS-CoV-2 main protease (Mpro) in pathogenesis being primarily involved in polyprotein processing and virus maturation, it makes SARS-CoV-2 main protease (Mpro) as an attractive and promising antiviral target. Thus, in our study, we focused on SARS-CoV-2 main protease (Mpro), used machine learning algorithms and virtually screened small derivatives of anthraquinolone and quinolizine from PubChem that may act as potential inhibitor. Prioritisation of cavity atoms obtained through pharmacophore mapping and other physicochemical descriptors of the derivatives helped mapped important chemical features for ligand binding interaction and also for synergistic studies with molecular docking. Subsequently, these studies outcome were supported through simulation trajectories that further proved anthraquinolone and quinolizine derivatives as potential small molecules to be tested experimentally in treating COVID-19 patients.

Synthesis of 7-azaindole based carbohydrazides and 1,3,4-oxadiazoles; Antioxidant activity, α-glucosidase inhibition properties and docking study

In this current work, 7-azaindole based 1,3,4-oxadiazoles have been successfully prepared by treatment of 3-(hydrazonomethyl)-7-azaindole with the different acyl chlorides or acetic anhydrides to give the corresponding carbohydrazides, followed by iodine mediated synthetic protocol in order to afford the corresponding 2,5-disubstituted 1,3,4-oxadiazoles. The full characterization data of the novel compounds were obtained by utilizing 1H NMR, 13C NMR, FT-IR, high-resolution mass spectrometry and single crystal X-ray diffraction techniques. The antioxidant activity and α-glucosidase inhibition potential of the prepared compounds are examined by in vitro assays. The targeted hydrazide linked 7-azaindoles and their corresponding cyclized form 1,3,4-oxadiazoles exhibited inhibitory potential with IC50 values ranges between 0.46 and 24.92 mM. Plausible binding mode and interaction of ligands with α-glucosidase enzyme have been studied by molecular docking, supporting the experimental results.

Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution

AbstractThe insertion of fluorine atoms and/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein–ligand binding interactions. However, this “magic effect” of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give “general guidelines” on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand–protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X‐ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand‐based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future.

Induction of apoptosis, cytotoxicity and radiosensitization by novel 3,4-dihydroquinazolinone derivatives

Twenty new quinazolinone derivatives bearing a piperonyl moiety were designed and synthesized. The structures of the target compounds were in agreement with the microanalytical and spectral data. Compounds 4-10, 13, 14 and 17-27 were screened for their cytotoxic activity against HepG-2 and MCF-7 cancer cell lines. The target compounds showed IC50 in the range of 2.46–36.85 µM and 3.87–88.93 µM for HepG-2 and MCF-7, respectively. The promising compounds 7, 19, 26 and 27 were selected to measure their EGFR inhibitory activity. The IC50 values of the promising compounds were in the range of 146.9–1032.7 nM for EGFR in reference to Erlotinib (IC50 = 96.6 nM). In further studies on compounds 7, 19, 26 and 27 using HepG-2 cell line, there was significant overexpression of p21 and downregulation of two members of IAPs protein family; Survivin and XIAP, relative to their controls. Annexin V-FITC and caspase-3 analyses have established a significant increase in early apoptosis. Moreover, the four selected compounds have impaired cell proliferation by cell cycle arrest at the G2/M phase compared to their respective control. Considering radiotherapy as the primary treatment for many types of solid tumors, the radiosensitizing abilities of compounds 7, 19, 26 and 27 were measured against HepG-2 and MCF-7 cell lines combined with a single dose of 8 Gy gamma radiation. Measurement of the IC50 of the promising compounds after irradiation revealed their ability to sensitize the cells to the lethal effect of gamma irradiation (IC50 = 1.56–4.32 µM and 3.06–5.93 µM for HepG-2 and MCF-7 cells, respectively). Molecular docking was performed to gain insights into the ligand-binding interactions of 7, 19, 26 and 27 inside the EGFR binding sites and revealed their essential interactions, explaining their good activity towards EGFR.