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Dietary compounds play an important role in the prevention and treatment of many cancers, although their specific molecular mechanism is not yet known. In the present study, thirty dietary agents were analyzed on nine drug targets through in silico studies. However, nine dietary scaffolds, such as silibinin, flavopiridol, oleandrin, ursolic acid, α-boswellic acid, β-boswellic acid, triterpenoid, guggulsterone, and oleanolic acid potentially bound to the cavity of PI3K-α, PKC-η, H-Ras, and Ras with the highest binding energy. Particularly, the compounds silibinin and flavopiridol have been shown to have broad spectrum anticancer activity. Interestingly, flavopiridol was embedded in the pockets of PI3K-α and PKC-η as bound crystal inhibitors in two different conformations and showed significant interactions with ATP binding pocket residues. However, complex-based pharmacophore modeling achieved two vital pharmacophoric features namely, two H-bond acceptors for PI3K-α, while three are hydrophobic, one cat-donor and one H-bond donor and acceptor for PKC-η, respectively. The database screening with the ChemBridge core library explored potential hits on a valid pharmacophore query. Therefore, to optimize perspective lead compounds from the hits, which were subjected to various constraints such as docking, MM/GBVI, Lipinski rule of five, ADMET and toxicity properties. Henceforth, the top ligands were sorted out and examined for vital interactions with key residues, arguably the top three promising lead compounds for PI3K-α, while seven for PKC-η, exhibiting binding energy from − 11.5 to − 8.5 kcal mol−1. Therefore, these scaffolds could be helpful in the development of novel class of effective anticancer agents. © 2021, The Author(s). We are grateful to the National Natural Science Foundation of China (grant numbers: 31071152 and 31171209) for providing research fund to WG.

Histone methyltransferases (HMTases) catalyze histone methylations that are the important epigenetic marks regulating gene expression, cell fate, and disease progression. In this study, we investigated potential epigenetic inhibitors against HMTases through in silico approaches, including ensembled molecular docking and molecular dynamics simulations (MDS).We identified three candidate compounds, including echinomycin, emetine, and streptonigrin, which showed interactions with HMTases. Echinomycin showed similar binding affinity with H3K4-HMTase NSD3 and H3K9-HMTase SETDB1 but streptonigrin and emetine had preferential binding affinity with NSD3 and SETDB1, respectively. The binding of NSD3 to streptonigrin and echinomycin and binding of SETDB1 to emetine and echinomycin were further confirmed by the results of hydrogen bonding profile and MM/PBSA calculations. Together, our results uncover the binding affinities of echinomycin, emetine, and streptonigrin with histone methyltransferases, and suggest that these compounds are potential epigenetic inhibitors regulating cell activities.

Enhancer of zeste homolog 2 (EZH2) is a histone H3 lysine 27 methyltransferases. Non-synonymous SNPs (nsSNPs) in the ezh2 gene may cause Weaver Syndrome that is a prominent and rare congenital disorder. Several EZH2 genetic variants have been characterized and reported, but there is no information available on their structural dynamics. Our study employs an in silico approach for structural and functional characterization of EZH2 nsSNPs. We identified 19 EZH2 nsSNPs majorly associated with Weaver Syndrome, among which four SET-domain nsSNPs including V621M, A677T, R679C, and H689Y significantly affected EZH2 structure. We conducted the triplicate of 100 ns of molecular dynamics simulations (MDS) to compare the dynamic interaction behaviors between wild-type and mutants of EZH2 with their substrate, H3K27me0 peptide. The simulation results revealed that the mutants had higher levels of structural variations as evidenced by secondary structure, density, distance plots, and principal component analysis. Compared to EZH2-WT, the mutants A677T and H689Y have shown lower binding energy with H3K27me0 peptide due to the denaturing of 310 helixes as exemplified by MM/PBSA calculations and secondary structure analysis. Our analysis shed light on mechanisms of structural variations of EZH2 nsSNPs and lay a stone to develop mutant-based therapeutic strategies for the design of target-specific scaffolds against Weaver Syndrome.

The present study was carried out with the specific aim to evaluate anti-Helicobacter pylori (Hp) and urease inhibitory activities of three flavonoids, namely 5-hydroxy-7,4′-dimethoxy-6,8-di-C-methylflavone (1), kaempferol-3-O-β-D-glucopyranoside (2) and kaempferol-3-O-α-L-rhamnopyranoside (3), of Syzygium alternifolium fruits. These flavonoids were examined for anti-H. pylori activity against two Hp strains, Hp 26695 and Hp P12, through a microbroth dilution assay with a time kill kinetics study and also the evaluation of their ability to lower H. pylori colonization with AGS (gastric epidermal cells). In addition, a urease inhibition assay was performed with these compounds, followed by 2D QSAR, molecular docking and molecular dynamics simulations on these compounds with target proteins, urease and cytotoxin associated gene (Cag A). The in vitro studies showed that compounds 2 and 3 show significant anti-H. pylori activity whereas compound 1 exhibits moderate activity when compared to amoxicillin and that these compounds also show strong bactericidal kinetics in a time dependent manner. These compounds potentially reduce the H. pylori colonization with a significant loss of its adhesion with AGS cells and inhibit the Hp urease activity. 2D QSAR analysis reveals that these compounds exhibit an acceptable correlation of RMSE = 0.905 and R2 = 0.820 with the biological assays. The compounds show strong inhibitions by forming H-bonding interactions with the active pocket residues of the target proteins as evidenced by 10 ns molecular dynamics simulations. Hence, the current investigation will provide a new vision for the discovery of potent antimicrobial agents from natural sources against H. pylori infections.

Multidrug resistant (MDR) gram negative bacterial infections are most prevalent in the hospitals which are truly untreatable and remedial verdict are very deprived. In the current investigation, two compounds (Quercetin and Pinitol) and fractions have been isolated and characterized from Indigofera barberi using chromatographic and NMR studies. Antimicrobial assays reveal IB-Me, IB-D and IB-E fractions and quercetin have shown eloquent antimicrobial activity on clinically isolated bacteria such as Pseudomonas aeruginosa, E. coli, Klebsiella pneumonia and Citrobacter sp. Molecular docking studies demonstrated quercetin has exhibited highest binding affinity with DNA gyrase B and subsequently eleven pharmacophore features viz . five HBD/HBA, two hydrophobic, one HBA and three aromatic (Pi) rings were identified using MOE. Pharmacophore based virtual screening, docking, binding energies and binding affinity with Born-volume (GB/VI) studies demonstrated thirteen lead molecules which were specifically interacted with Asn46, Asp73, Arg76, Thr163, Lys103, Arg136 residues and conserved water molecules within ATP pocket of DNA gyrase B. These scaffolds comply with Lipinski rule of five, toxicity and drug likeness properties deliberated as drug compounds. Hence, these compounds could be endorsed as persuasive DNA gyrase B inhibitors which can be considered as novel compounds in the clinical management of MDR Gram negative bacterial infections.

Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane α-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds.

Continuous usage of synthetic chemotherapeutic drugs causes adverse effects, which prompted for the development of alternative therapeutics for gastric cancer from natural source. This study was carried out with a specific aim to screen gastroprotective compounds from the fruits of Syzygium alternifolium (Myrtaceae). Three flavonoids, namely, 1) 5-hydroxy-7,4′-dimethoxy-6,8-di-C-methylflavone, 2) kaempferol-3-O-β-d-glucopyranoside, and 3) kaempferol-3-O-α-l-rhamnopyranoside were isolated from the above medicinal plant by employing silica gel column chromatography and are characterized by NMR techniques. Antigastric cancer activity of these flavonoids was examined on AGS cell lines followed by cell cycle progression assay. In addition, pharmacophore-based screening and molecular dynamics of protein–ligand complex were carried out to identify potent scaffolds. The results showed that compounds 2 and 3 exhibited significant cytotoxic effect, whereas compound 1 showed moderate effect on AGS cells by inhibiting G2/M phase of cell cycle. Molecular docking analysis revealed that compound 2 has higher binding energies on human growth factor receptor-2 (HER2). The constructed pharmacophore models reveal that the compounds have more number of H-bond Acc/Don features which contribute to the inhibition of HER2 activity. By selecting these features, 34 hits were retrieved using the query compound 2. Molecular dynamic simulations (MDS) of protein–ligand complexes demonstrated conspicuous inhibition of HER2 as evidenced by dynamic trajectory analysis. Based on these results, the compound ZINC67903192 was identified as promising HER2 inhibitor against gastric cancer. The present work provides a basis for the discovery a new class of scaffolds from natural products for gastric carcinoma.