In vitro evaluation, molecular docking, and molecular dynamics studies of resorcinol derivatives against yeast α‐glucosidase

Recent studies have revealed that MERTK and BRAF V600E receptors have been found to be over-expressed in several types of cancers including melanoma, making these receptors targets for drug design. In this study, we have designed novel peptide conjugates with the natural products vanillic acid, thiazole-2-carboxylic acid, cinnamic acid, theanine, and protocatechuic acid. Each of these compounds was conjugated with the tumor targeting peptide sequence TAASGVRSMH, known to bind to NG2 and target tumor neovasculature. We examined their binding affinities and stability with MERTK and BRAF V600E receptors using molecular docking and molecular dynamics studies. Compared to the neat compounds, the peptide conjugates displayed higher binding affinity toward both receptors. In the case of MERTK, the most stable complexes were formed with di-theaninate-peptide, vanillate-peptide, and thiazole-2-amido peptide conjugates and binding occurred in the hinge region. Additionally, it was discovered that the peptide alone also had high binding ability and stability with the MERTK receptor. In the case of BRAF V600E, the peptide conjugates of protocatechuate, vanillate and thiazole-2-amido peptide conjugates showed the formation of the most stable complexes and binding occurred in the ATP binding cleft. Further analysis revealed that the number of hydrogen bonds and hydrophobic interactions played a critical role in enhanced stability of the complexes. Docking studies also revealed that binding affinities for NG2 were similar to MERTK and higher for BRAF V600E. MMGBSA studies of the trajectories revealed that the protocatechuate-peptide conjugate showed the highest binding energy with BRAF V600E while the peptide-TAASGVRSMH showed the highest binding energy with MERTK. ADME studies revealed that each of the compounds showed medium to high permeability toward MDCK cells and were not hERG blockers. Furthermore, the conjugates were not CYP inhibitors or substrates, but they were found to be Pgp substrates. Our results indicated that the protocatechuate-TAASGVRSMH, thiazole-2-amido-TAASGVRSMH, and vanillate-TAASGVRSMH conjugates may be furthered developed for in vitro and in vivo studies as novel tumor targeting compounds for tumor cells over-expressing BRAF V600E, while di-theaninate-amido-TAASGVRSMH and thiazole-2-amido-TAASGVRSMH conjugates may be developed for targeting MERTK receptors. These studies provide insight into the molecular interactions of natural product-peptide conjugates and their potential for binding to and targeting MERTK and BRAF V600E receptors in developing new therapeutics for targeting cancer.

This research aims to find natural product compounds that have the potential to act as MAO-B inhibitors that are useful in the treatment of neurodegenerative diseases, through the stages: a) Virtual Screening, b) Molecule Docking, c) Pharmacokinetic and toxicity prediction, and d) Simulation approach Molecular dynamics.The research steps include the following steps: a) searching for molecules in the ZINC15 data base that are similar to the natural ligand molecule (safinamide) obtained from the protein data bank (PDB code: 2v5z) and the control ligand L-DOPA. A total of 481 molecules were downloaded from the data base and then molecular docking was carried out using the autodock program on the MAO-B target in the 2v5z receptor. After carrying out the docking analysis, 48 ligand molecules were selected which had a binding affinity (DG/kcal/mol) that was smaller than the DG of the natural ligand and the control ligand and nine (9) ligand molecules were taken to be tested: (i) ligand-ligand interactions MAO-B with discovery studio, (ii) Absorption, Distribution, Metabolism and Excretion properties with SwissADME and (iii) toxicity using PROTOX-II. Molecular dynamics simulations were carried out to determine the stability of ligands in proteins. Ligand complex [CC(C)c1ccc(NC(=O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)cc1]-2v5z was chosen to simulate for 100 ps. The results of the molecular docking study showed that there were 9 molecules that had binding affinity values that were smaller than the binding affinity of the natural ligand and the control ligand. Ligand and residue interactions are dominated by hydrogen bonds, donor-donor and pi-pi stacked interactions. Based on SwissADME, the Blood Brain Barrier (BBB) permeant on ligand number 1, 2, 3, 5, 6, and 9 shows that it is orally active and cannot pass through the BBB and will not cause any side effects, whereas ligand number 4, 7, 8, 10, and 11 can cross the BBB and may cause side effects. Based on the results of toxicity prediction (PROTOX-II), it is known that there are four (4) ligands in class V, five (5) ligands in class IV and the rest in class II. Hepatotoxicity, carcinogenicity, and Phosphoprotein (Tumor Suppressor) p53 in eleven ligands are predicted to be inactive and have a small probability. The stimulated [CC(C)c1ccc(NC(=O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)cc1]-2v5z complex apparently still shows ligand-protein fluctuations so that its conformation is still unstable.

Although cancer continues to be one of the world’s major causes of death, current cancer drugs have many serious side effects. There remains a need for new anticancer agents to overcome these shortcomings. Alternaria is one of the most widespread fungal genera, many species of which produce several classes of metabolites with potential polypharmacological activities. A few quinones and pyrones from Alternaria spp. have proven to exert cytotoxic effects against certain cancer cell lines, but their molecular mode of action is not known. The current study aimed to investigate the potential mechanisms that underlie the anticancer activity of a few selected quinones and pyrones from Alternaria solani and Alternaria alternata by molecular docking and dynamic simulation approaches. The selected metabolites were screened for their binding affinity to Heat shock protein 90 (HSP90), which is a known anticancer drug target. Molecular docking studies have revealed that Macrosporin, Altersolanol B, Fonsecin, and Neoaltenuene have good binding affinities with the target protein and the stabilities of the formed complexes were evaluated through molecular dynamics simulations. By analyzing the Root Mean Square Distance (RMSD), Root Mean Square Fluctuation (RMSF), and Principal Component Analysis (PCA) plots obtained from molecular dynamics simulations, this study shows that the complexes of all 4 lead molecules with target protein are stable over a 100 ns period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were used to compute the binding free energies. The lead molecules were studied using in-silico analysis to determine their drug-likeness based on their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and physicochemical properties. The results demonstrate that Macrosporin, Fonsecin, and Neoaltenuene could become promising anticancer molecules that target HSP90. Communicated by Ramaswamy H. Sarma

Context: The search for antidiabetic drugs that target the receptors involved in diabetes has received significant attention in recent years. Peperomia pellucida (L.) Kunth's ethanol extract and ethyl acetate fraction have antihyperglycemic activity. 8,9-dimethoxy ellagic acid (DEA) has shown significant diabetes mellitus activity in mice, but its interaction with diabetes receptors remains unknown. Aims: To perform molecular docking and molecular dynamics simulations to explore the binding interactions and stability of DEA within the binding sites of enzymes involved in diabetes. Methods: At the outset, the utilization of molecular docking was limited to forecasting the DEA's binding orientations and affinities within the active sites of the enzymes implicated in diabetes. Following this, molecular dynamics simulation was employed to investigate the interactions, stability, and dynamic behavior of these complexes over a period of 100 nanoseconds. Results: Molecular docking results revealed that DEA interacts with all selected receptors involved in diabetes and interacts more strongly with the aldose reductase receptor (PDB ID 3S3G) than the native ligand, with a binding energy of -10.3 kcal/mol. However, further molecular dynamics simulations confirmed the stability of the receptor complex with DEA over 100 ns, which is less potent than that of the native ligand. This is probably due to the rigidity of the DEA molecular structure. Conclusions: This study highlights the potential of DEA derived from P. pellucida as an inhibitor of various receptors involved in diabetes.

Mechanism of Keke tablets in treating post-infectious cough following influenza A virus infection based on network pharmacology, molecular docking, molecular dynamics and in vivo experiments.

Design, synthesis, and inhibition of α-glucosidase by novel l-phenylalanine-derived hydrazones: Kinetic, molecular docking, and dynamics studies.

Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies

Cerebral malaria (CM) is a severe manifestation of parasite infection caused by Plasmodium species. In 2018, there were approximately 228 million malaria cases worldwide, resulting in about 405,000 deaths. Survivors of CM may live with lifelong post-CM consequences apart from an increased risk of childhood neurodisability. EphA2 receptors have been linked to several neurological disorders and have a vital role in the CM-associated breakdown of the blood–brain barrier. Molecular docking (MD) studies of phytochemicals from Taraxacum officinale, Tinospora cordifolia, Rosmarinus officinalis, Ocimum basilicum, and the native ligand ephrin-A were conducted to identify the potential blockers of the EphA2 receptor. The software program Autodock Vina 1.1.2 in PyRx-Virtual Screening Tool and BIOVIA Discovery Studio visualizer was used for this MD study. The present work showed that blocking the EphA2 receptor by these phytochemicals prevents endothelial cell apoptosis by averting ephrin-A ligand-expressing CD8+ T cell bioadhesion. These phytochemicals showed excellent docking scores and binding affinity, demonstrating hydrogen bond, electrostatic, Pi-sigma, and pi alkyl hydrophobic binding interactions when compared with native ligands at the EphA2 receptor. The comparative MD study using two PDB IDs showed that isocolumbin, carnosol, luteolin, and taraxasterol have better binding affinities (viz. −9.3, −9.0, −9.5, and −9.2 kcal/mol, respectively). Ocimum basilicum phytochemicals showed a lower docking score but more binding interactions than native ligands at the EphA2 receptor for both PDB IDs. This suggests that these phytochemicals may serve as potential drug candidates in the management of CM. We consider that the present MD study provides leads in drug development by targeting the EphA2 receptor in managing CM. The approach is innovative because a role for EphA2 receptors in CM has never been highlighted.

Lophosoria quadripinnata (J.F.Gmel.) C.Chr., a fern species from the Dicksoniaceae family, is widely distributed in Central and South America. This study aimed to identify the bioactive compounds in the aqueous extract of L. quadripinnata, evaluate its antioxidant potential through in vitro analysis, and assess its neuroprotective effects via molecular docking and dynamics studies. Fourteen compounds were identified using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-ESI-QToF-MS). In vitro assays revealed high concentrations of phenolic and flavonoid compounds, alongside significant antioxidant activity. Molecular docking studies, involving acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, and the Nrf2-Keap1 protein complex, identified three compounds-5C3M (5-O-caffeoyl-3-O-malonylquinic acid), 5GDC (5-O-glucoside-6,7-dimethoxycoumarin), and irifloside-as promising inhibitors. These compounds exhibited favorable binding affinities, minimal toxicity, and strong interactions with key residues involved in the inhibition of the enzymes and protein complex. Additionally, molecular dynamics simulations revealed stable binding with AChE, BChE, and tyrosinase, with irifloside showing the highest binding affinity. The compounds also demonstrated the ability to modulate the Nrf2-Keap1 pathway, potentially enhancing the cellular antioxidant response. These findings suggest that L. quadripinnata contains bioactive compounds with significant potential for the development of neuroprotective agents, especially in oxidative stress-related diseases such as Alzheimer's and Parkinson's.

Background and objective: To recognize natural phytochemicals from medicinal plants, in order to reutilize them against COVID-19 by the virtue of molecular dynamics (MD) simulation study and molecular docking study COVID-19 is a transmissible disease that is initiated and propagated through a new virus strain SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2). Since 31st December 2019 in Wuhan city of China and the infection has outspread globally infecting many countries. Methods: Molecular dynamics MD simulation interaction analysis, Salt bridge analysis, Flexibility analysis, Ace-2- rbd complex electrostatic component of binding energy calculation method. Results: Molecular docking studies has shown to be having two inhibitors against SARS-CoV-2 Mpro (Main protease), from Withania somnifera (Ashwagandha) (Withanoside V [10.32 kcal/mol] and Somniferine [9.62 kcal/mol]). Inconsolably, SARS-CoV-2 infection in patients with pre-existing disease conditions (e.g., hypertension and diabetes) can cause severe complications and, as a result, mortality. Conclusion: Hence from the present study it could be suggested that, the active phytochemicals from medicinal plants could potentially inhibit Mpro of SARS-CoV-2 and further equip the management strategy against COVID-19-a global contagion. Active phytoconstituents of Ayurvedic medicinal plants Withania somnifera (Ashwagandha) predicted to significantly hinder main protease (Mpro or 3Clpro) of SARS-CoV-2.Through molecular docking and molecular dynamic simulation study, Withanoside V, Somniferine were observed to impede the activity of SARS-CoV-2 Mpro.

The epidermal growth factor receptor (EGFR), a protein located on the cell surface, belongs to the tyrosine kinase family and plays a crucial role in cell development and proliferation. Abnormal expression or mutations in the EGFR gene can lead to non–small cell lung cancer. Although established EGFR inhibitors have been effective in the treatment of cancer, they are associated with several side effects. As a result, there is an urgent need to develop novel EGFR inhibitors that can effectively target the receptor while causing no adverse side effects. In this study, a series of bis(6‐amino‐1,3‐dimethylpyrimidine‐2,4(1H,3H)‐dione derivatives was synthesized in water at room temperature without the use of any catalyst, and pharmaceutical properties are investigated. Computational methods, including density functional theory (DFT), molecular docking, and molecular dynamics (MD), were utilized to investigate the chemical properties, drug‐like characteristics, and anticancer potential of the molecule. Quantum chemical calculations indicated that the molecules are relatively stable and exhibit significant electrophilic properties. The analysis of HOMO‐LUMO contour maps was conducted to illustrate charge density distributions that may be associated with biological activity. Docking studies with EGFR enzymes indicated that all compounds demonstrated favorable binding affinities, with docking scores ranging from −4.412 to −6.158 kcal/mol. Particularly, Compound 3f, with an energy of −6.158 kcal/mol, showed the best binding affinity, outperforming the native ligand, which had a docking score of −5.076 kcal/mol. The stability of the EGFR‐3f complex is significantly enhanced by the formation of five conventional hydrogen bonds and one carbon–hydrogen bond in ligand–protein interactions. MD simulations, which included analyses such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), molecular surface area (MolSA), and polar surface area (PSA), were conducted on the EGFR‐3f complex. It was found that the EGFR‐3f complex is stable, and the results show that Compound 3f has a strong interaction with the target enzyme.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) partial agonists or antagonists, also termed as selective PPAR-γ modulators, are more beneficial than full agonists because they can avoid the adverse effects associated with PPAR-γ full agonists, such as weight gain and congestive heart disorders, while retaining the antidiabetic efficiency. In this study, we designed and synthesized new benzylidene-thiazolidine-2,4-diones while keeping the acidic thiazolidinedione (TZD) ring at the center, which is in contrast with the typical pharmacophore of PPAR-γ agonists. Five compounds (5a–e) were designed and synthesized in moderate to good yields and were characterized using spectral techniques. The in vivo antidiabetic efficacy of the synthesized compounds was assessed on streptozotocin-induced diabetic mice using standard protocols, and their effect on weight gain was also studied. Molecular docking and molecular dynamics (MD) simulation studies were performed to investigate the binding interactions of the title compounds with the PPAR-γ receptor and to establish their binding mechanism. Antidiabetic activity results revealed that compounds 5d and 5e possess promising antidiabetic activity comparable with the standard drug rosiglitazone. No compound showed considerable effect on the body weight of animals after 21 days of administration, and the findings showed statistical difference (p < 0.05 to p < 0.0001) among the diabetic control and standard drug rosiglitazone groups. In molecular docking study, compounds 5c and 5d exhibited higher binding energies (− 10.1 and − 10.0 kcal/mol, respectively) than the native ligand, non-thiazolidinedione PPAR-γ partial agonist (nTZDpa) (− 9.8 kcal/mol). MD simulation further authenticated the stability of compound 5c-PPAR-γ complex over the 150 ns duration. The RMSD, RMSF, rGyr, SASA, and binding interactions of compound 5c-PPAR-γ complex were comparable to those of native ligand nTZDpa-PPAR-γ complex, suggesting that the title compounds have the potential to be developed as partial PPAR-γ agonists.

Kinesin Eg5 plays an essential role in the early stages of mitosis, and it is an interesting drug target for the design of potent inhibitors. In this work, combined molecular modeling studies of molecular docking, receptor-guided QSAR methodology, and molecular dynamics (MD) simulation were performed on a series of novel S-trityl-l-cysteine (STLC) analogues as Eg5 inhibitors to understand the structural features and key residues which are involved in the inhibition. Molecular docking study was used to find the actual conformations of STLC analogues in the binding site of Eg5. Multiple linear regression (MLR), artificial neural network (ANN), and support vector machine (SVM) models were developed by the conformation which was obtained by performing docking studies. The satisfactory result of the SVM model (R2 = 0.962, SE = 0.210, RMSE = 0.190, and Q2LOO = 0.930) demonstrated the superiority of this model over other models. Also, the satisfactory agreement between experiment and predicted inhibitory values suggested that the SVM model represents good correlation and predictive power. Molecular docking was used to study the functionalities of active molecular interaction between inhibitors and Eg5. Moreover, molecular dynamics (MD) simulation was performed on the best inhibitor-Eg5 complex to investigate the stability of docked conformation and to study the binding interactions in detail. The MD simulation result showed four hydrogen bond interactions with Eg5 residues including Gly117, Glu116, Gly117, and Glu118. The outcome of this study can be used as a guideline to better interpret the protein-ligand interaction and also can assist in the designing and development of more potent Eg5 inhibitors.

1-Ethoxycarbonyl-beta-carboline inhibits the M2 polarization of tumor-associated macrophages: A study based on network pharmacology and molecular docking analyses

Due to the unavailability specific drugs or vaccines (FDA approved) that can cure COVID-19, the development of potent antiviral drug candidates/therapeutic molecules against COVID-19 is urgently required. This study was aimed at in silico screening and study of polyphenolic phytochemical compounds in a rational way by virtual screening, molecular docking and molecular dynamics studies against SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) enzymes. The objective of the study was to identify plant-derived polyphenolic compounds and/or flavonoid molecules as possible antiviral agents with protease inhibitory potential against SARS-CoV-2. In this study, we report plant-derived polyphenolic compounds (including flavonoids) as novel protease inhibitors against SARS-CoV-2. From virtual docking and molecular docking study, 31 polyphenolic compounds were identified as active antiviral molecules possessing well-defined binding affinity with acceptable ADMET, toxicity and lead-like or drug-like properties. Six polyphenolic compounds, namely, enterodiol, taxifolin, eriodictyol, leucopelargonidin, morin and myricetin were found to exhibit remarkable binding affinities against the proteases with taxifolin and morin exhibiting the highest binding affinity toward Mpro and PLpro respectively. Molecular dynamics simulation studies of these compounds in complex with the proteases showed that the binding of the compounds is characterized by structural perturbations of the proteases suggesting their antiviral activities. These compounds can therefore be investigated further by in vivo and in vitro techniques to assess their potential efficacy against SARS-CoV-2 and thus serve as the starting point for the development of potent antiviral agents against the deadly COVID-19. Communicated by Ramaswamy H. Sarma