Modified D-Glucofuranoses as New Black Fungus Protease Inhibitors: Computational Screening, Docking, Dynamics, and QSAR Study

Simulation and computational analysis of 6-gingerol and 6-shogaol is done to evaluate their binding affinity against ERα. Active site prediction was done using Computed Atlas of Surface Topography of Proteins (CASTp) to determine the binding pocket of ERα. Molecular docking and molecular dynamics (MD) simulation were done to assess the binding affinity and stability of the ligand-ERα complexes formed. Results showed that Tamoxifen have lowest binding energy (-9.61 ± 0.39 kcal/mol) followed by 6-gingerol (-6.59 ± 0.29 kcal/mol) and 6-shogaol (-5.70 ± 0.36 kcal/mol). Inhibition constant (Ki) range of TMX-ERα was found to be drastically lower than both 6GN-ERα and 6SG-ERα. Based on the difference in the binding energy range and inhibition constant, 6-gingerol and 6-shogaol showed less potential in substituting tamoxifen for the inhibition of ERɑ. Docking complexes formed was supported with stability in root mean square deviation (RMSD) and total binding energy of the complexes. The study is concluded that 6-gingerol have high level of interactions with the ERα active site in terms of hydrogen bonding whereas hydrophobic interactions are observed with both 6-gingerol and 6-shogaol. However, both ginger bioactive compounds poses low potential as substitute in comparison with tamoxifen against ERα.

The "Black and White Fungus" is a very infrequently developing pathogen with a high fatality rate that has prompted widespread public health concern during the period of the COVID-19 pandemic. This pathogenic fungus may be widely distributed in nature, in plants, and in deteriorating fruits and vegetables because of its widespread nature. Numerous sugar molecules, such as glucopyranoside and glucofuranose, have been reported to have significant antibacterial, antifungal, and antiviral activity, and they were also revealed to be able to inhibit multidrug-resistant microorganisms. The recent black fungus epidemic was extremely serious in India, combined with COVID-19, which contributed to the high mortality impact and deterioration of the situation due to the unavailability of effective treatments. So, rhamnopyranose type derivatives 1–9 were studied against the proteins associated with black and white fungi such as Mycolicibacterium smegmatis (PDB ID 7D6X), Rhizomucor miehei (PDB ID 4WTP), Candida auris (PDB ID 6U8J), and Aspergillus luchuensis (PDB 1BK1). These compounds exhibited favorable physical and biochemical scores, as well as appropriate ADMET metrics, among other characteristics. Following the molecular docking procedure, it was found that 1–9 had the highest binding affinity in most cases, (> -6.00 kcal/mol), while compound 9 had outstanding binding affinity against Rhizomucor miehei (-8.7 kcal/mol) and against Mycolicibacterium smegmatis (-8.2 kcal/mol). In addition, the binding affinity against white fungus is also outstanding. This time, compounds 8 and 9 had better binding energy, which is -7.8 kcal/mol against Aspergillus luchuensis (1BK1) and -7.6 kcal/mol against Candida auris (6U8J). Finally, the molecular dynamics simulation at 100 ns has proved that they are stable for new medication development. Among the derivatives 1–9, ligands 8 and 9 exhibited potential medicinal characteristics when all of the data were considered.

During the second phase of SARS-CoV-2, an unknown fungal infection, identified as black fungus, was transmitted to numerous people among the hospitalized COVID-19 patients and increased the death rate. The black fungus is associated with the Mycolicibacterium smegmatis, Mucor lusitanicus, and Rhizomucor miehei microorganisms. At the same time, other pathogenic diseases, such as the Monkeypox virus and Marburg virus, impacted global health. Policymakers are concerned about these pathogens due to their severe pathogenic capabilities and rapid spread. However, no standard therapies are available to manage and treat those conditions. Since the coptisine has significant antimicrobial, antiviral, and antifungal properties; therefore, the current investigation has been designed by modifying coptisine to identify an effective drug molecule against Black fungus, Monkeypox, and Marburg virus. After designing the derivatives of coptisine, they have been optimized to get a stable molecular structure. These ligands were then subjected to molecular docking study against two vital proteins obtained from black fungal pathogens: Rhizomucor miehei (PDB ID: 4WTP) and Mycolicibacterium smegmatis (PDB ID 7D6X), and proteins found in Monkeypox virus (PDB ID: 4QWO) and Marburg virus (PDB ID 4OR8). Following molecular docking, other computational investigations, such as ADMET, QSAR, drug-likeness, quantum calculation and molecular dynamics, were also performed to determine their potentiality as antifungal and antiviral inhibitors. The docking score reported that they have strong affinities against Black fungus, Monkeypox virus, and Marburg virus. Then, the molecular dynamic simulation was conducted to determine their stability and durability in the physiological system with water at 100 ns, which documented that the mentioned drugs were stable over the simulated time. Thus, our in silico investigation provides a preliminary report that coptisine derivatives are safe and potentially effective against Black fungus, Monkeypox virus, and Marburg virus. Hence, coptisine derivatives may be a prospective candidate for developing drugs against Black fungus, Monkeypox and Marburg viruses.

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

Potential inhibitory activity of phytoconstituents against black fungus: In silico ADMET, molecular docking and MD simulation studies

Exploration of Canarium odontophyllum fruit phytoconstituents as potential candidates against epilepsy using in silico studies

Potential inhibitors of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro/ 3CLpro: molecular docking and simulation studies of three pertinent medicinal plant natural components

Rheumatoid arthritis (RA) remains a significant therapeutic challenge due to its chronic inflammatory nature. Consequently, many patients turn to alternative therapies, such as herbal compounds and supplements, when conventional treatments prove relatively ineffective or cause adverse side effects. Some compounds are being investigated for their potential to alleviate RA symptoms or manage disease. This study aimed to evaluate the anti-inflammatory effects of selected herbal compounds targeting the Interleukin-1 (IL-1) and Interleukin-6 (IL-6) pathways, key inflammatory regulators in RA. Specifically, the study assessed the binding affinity, stability, and dynamics of IL-1 and IL-6 inhibitory compounds as potential therapeutic agents for RA. In silico experiments were conducted with herbal compounds to modulate IL-1 and IL-6 signaling. Computational techniques, including molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations, Absorption, Distribution, Metabolism, and Excretion (ADME) analysis, toxicity predictions, and Density Functional Theory (DFT) analysis, were employed to investigate these interactions comprehensively. Neoglucobrassicin demonstrated the strongest binding affinity for IL-6 (Total score: -349.00 kJ/mol), followed by Galbelgin (-338.00 kJ/mol). For IL-1β, CID21722980 exhibited the highest binding affinity (-273.14 kJ/mol), with Eupaformosanin ranking second (-264.29 kJ/mol). Neoglucobrassicin formed interactions with multiple IL-6 residues, indicating a stable binding complex, while CID21722980 similarly interacted with key IL-1β residues, forming stable complexes. Both the Neoglucobrassicin-IL-6 and CID21722980- IL1β complexes demonstrated structural stability, as evidenced by Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) stabilizing towards the end of the 100 ns molecular dynamics (MD) simulation. MM-GBSA analysis revealed the highest binding energy for the IL-6-Neoglucobrassicin complex (-43.70 kcal/mol), while CID21722980 showed strong affinity for IL-1β (-43.29 kcal/mol), suggesting enhanced binding potential. Additionally, Density Functional Theory (DFT) analysis of the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) energies revealed electron distribution patterns in Neoglucobrassicin and CID21722980 that support their potential therapeutic applications. The strong binding affinities, stable molecular dynamics (MD) simulations, and favorable ADMET and DFT properties of Neoglucobrassicin and CID21722980 underscore their potential as antiinflammatory agents targeting IL-6 and IL-1β. The mechanistic insights into their inhibitory effects on these targets suggest multifaceted anti-inflammatory properties, warranting further in vivo and clinical investigations. Neoglucobrassicin and CID21722980 demonstrated promising binding affinities, favorable pharmacokinetic profiles, and advantageous electronic properties, positioning them as strong candidates for further exploration in anti-inflammatory therapies. These findings highlight the potential of these herbal compounds as modulators of IL-6 and IL-1β, paving the way for future drug development.

Discovery of putative inhibitors of human Pkd1 enzyme: Molecular docking, dynamics and simulation, QSAR, and MM/GBSA

The study aimed to screen prospective molecular targets of BCC and potential natural lead candidates as effective binders by computational modeling, molecular docking, and dynamic (MD) simulation studies. Based on the virulent functions, tRNA 5-methylaminomethyl-2-thiouridine biosynthesis bifunctional protein (mnmC) and pyrimidine/purine nucleoside phosphorylase (ppnP) were selected as the prospective molecular targets. In the absence of experimental data, the three-dimensional (3D) structures of these targets were computationally predicted. After a thorough literature survey and database search, the drug-likeness, and pharmacokinetic properties of 70 natural molecules were computationally predicted and the effectual binding of the best lead molecules against both the targets was predicted by molecular docking. The stabilities of the best-docked complexes were validated by MD simulation and the binding energy calculations were carried out by MM-GBSA approaches. The present study revealed that the hypothetical models of mnmC and ppnP showed stereochemical accuracy. The study also showed that among 70 natural compounds subjected to computational screening, Honokiol (3',5-Di(prop-2-en-1-yl) [1,1'-biphenyl]-2,4'-diol) present in Magnolia showed ideal drug-likeness, pharmacokinetic features and showed effectual binding with mnmC and ppnP (binding energies -7.3kcal/mol and -6.6kcal/mol, respectively). The MD simulation and GBSA calculation studies showed that the ligand-protein complexes stabilized throughout tMD simulation. The present study suggests that Honokiol can be used as a potential lead molecule against mnmC and ppnP targets of BCC and this study provides insight into further experimental validation for alternative lead development against drug resistant BCC.

ObjectiveWith the aim of clarifying the therapeutic mechanisms of the American Ginseng-Achyranthes bidentata (AG&A) herbal pair in primary Sjögren’s syndrome (pSS), this study employs an integrated approach combining network pharmacology, molecular docking, molecular dynamics simulations, and animal experiments.MethodsNetwork pharmacology & LC-MS/MS was utilized to identify the active components and potential targets of A&A. Molecular docking and dynamics simulations were performed to evaluate binding affinity and complex stability with key targets. Animal experiments using non-obese diabetic (NOD) mice were conducted to validate symptom improvement by critical active components.ResultsNetwork pharmacology identified baicalin and quercetin as key active components. Molecular docking revealed strong binding affinities (binding energy ≤ -8.0 kcal/mol) between these compounds and apoptosis-related proteins, BAX and CASP3. Molecular dynamics simulations confirmed the stability of these complexes. Animal experiments demonstrated that baicalin can significantly reduce inflammatory cytokines of IL-18, TNF-α, IFN-α, and IFN-β,CXCL-10 (p < 0.05), decrease mtDNA release, and downregulate cGAS-STING pathway-related proteins including cGAS, STING, CASP3, ZBP1, TBK1, p-STING, p-TBK1, IRF3, p-IRF3 and BAX.ConclusionThe critical components baicalin and quercetin from AG&A, particularly in aqueous extracts, exhibit therapeutic efficacy against pSS. This study provides experimental evidence for their action mechanism through modulating the mtDNA-cGAS-STING pathway. While highlighting their therapeutic potential, additional in vivo and clinical studies are warranted to validate these findings.

The novel strain of human coronavirus, emerged in December 2019, which has been designated as SARS-CoV-2, causes a severe acute respiratory syndrome. Since then, it has arisen as a serious threat to the world public health. Since no approved vaccines or drugs has been found to efficiently stop the virulent spread of the virus, progressive inquiries targeting these viruses are urgently needed, especially those from plant sources. Metabolic profiling using LC-HR-ESI-MS of the butanol extract of Ocimum menthiifolium (Lamiaceae) aerial parts yielded 10 compounds including flavonoids, iridoids and phenolics. As it has been previously reported that some flavonoids can be used as anti-SARS drugs by targeting SARS-CoV-1 3CLpro, we chose to examine 14 flavonoids (detected by metabolomics and other compounds isolated via several chromatographic techniques). We investigated their potential binding interactions with the 4 main SARS-CoV-2 targets: Mpro, nsp16/nsp10 complex, ACE2-PD and RBD-S-protein via molecular docking. Docking results indicated that the nsp16/nsp10 complex has the best binding affinities where the strongest binding was detected with apigenin-7-O-rutinoside, prunin and acaciin with −9.4, −9.3 and −9.3 kcal/mol binding energy, respectively, compared to the control (SAM) with −8.2 kcal/mol. Furthermore, the stability of these complexes was studied using molecular dynamics of 150 ns, which were then compared to their complexes in the other three targets. MM-PBSA calculations suggested the high stability of acaciin-nsp16 complex with binding energy of −110 kJ/mol. This study sheds light on the structure-based design of natural flavonoids as anti-SARS-CoV-2 drugs targeting the nsp16/10 complex. Communicated by Ramaswamy H. Sarma

This study evaluates radioiodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for HER2-targeted cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment of HER2-positive cancers. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds’ binding affinities and mechanisms to the HER2 receptor compared to lapatinib, a known HER2 inhibitor. Molecular docking studies identified [125I]epirubicin with the highest ΔGbind (−10.92 kcal/mol) compared to lapatinib (−10.65 kcal/mol) and [125I]anastrozole (−9.65 kcal/mol). However, these differences were not statistically significant. Further molecular dynamics (MD) simulations are required to better understand the implications of these findings on the therapeutic potential of the compounds. MD simulations affirmed a stable interaction with the HER2 receptor, indicated by an average RMSD of 4.51 Å for [125I]epirubicin. RMSF analysis pointed to significant flexibility at key receptor regions, enhancing the inhibitory action against HER2. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions. The average Rg values for [125I]anastrozole and [125I]epirubicin complexes suggest a modest increase in structural flexibility without compromising protein compactness, reflecting their potential to induce necessary conformational changes in the HER2 receptor function. These analyses reveal enhanced flexibility and specific receptor region interactions, suggesting adaptability in binding, which could augment the inhibitory action against HER2. MM-PBSA calculations indicate the potential of these radioiodinated compounds as HER2 inhibitors. Notably, [125I]epirubicin exhibited a free binding energy of −65.81 ± 0.12 kJ/mol, which is comparable to lapatinib at −64.05 ± 0.11 kJ/mol and more favorable than [125I]anastrozole at −57.18 ± 0.12 kJ/mol. The results suggest electrostatic interactions as a major contributor to the binding affinity. The computational analysis underscores that [125I]anastrozole and [125I]epirubicin may have a promising role as HER2 inhibitors, especially [125I]epirubicin due to its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the HER2 receptor. To validate these computational predictions and evaluate the therapeutic potential of these compounds for HER2-targeted cancer therapy, it is essential to conduct empirical validation through both in vitro and in vivo studies.

This study examined the binding affinities and therapeutic potential of natural products targeting pain-related receptors using molecular docking and molecular dynamics (MD) simulations. Drug-like properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were also conducted. AutoDock Vina (The Scripps Research Institute, La Jolla, CA, USA) was used for docking against pain-related receptors, including transient receptor potential vanilloid 1 (TRPV1), cyclooxygenase-2 (COX-2), cannabinoid receptor 1 (CB1), mu-opioid receptor, and nicotinic acetylcholine receptors. Celecoxib was included as a reference drug for docking score comparison. Protein-ligand complex stability was assessed via 100-nanosecond (ns) MD simulations using GROMACS (GROningen MAchine for Chemical Simulations; the University of Groningen, Netherlands), analyzing root mean square deviation (RMSD) and radius of gyration (Rg). Drug-likeness was evaluated by Lipinski's rule of five, and ADMET analysis was performed for pharmacokinetics and toxicity profiling. Ginsenoside Rb1 exhibited a strong affinity for TRPV1 (-9.5 kcal/mol) and mu-opioid (-9.0 kcal/mol) receptors, suggesting its potential as a non-opioid analgesic candidate. Cyanidin 3-O-rutinoside demonstrated high binding to TRPV1 (-9.35 kcal/mol), COX-2 (-9.65 kcal/mol), and CB1 (-9.18 kcal/mol), surpassing the reference drug celecoxib (-7.22 kcal/mol) in COX-2 binding. MD simulations confirmed complex stability, with RMSD (~3.0 Å) and Rg (~3.0 nm) values lower than unbound proteins. Most compounds met Lipinski's criteria, indicating good oral bioavailability. ADMET analysis revealed favorable absorption and distribution with low toxicity. Ginsenoside Rb1 and cyanidin 3-O-rutinoside exhibit high binding affinity, stability, and favorable pharmacokinetic properties, supporting their potential as non-opioid analgesic candidates. Their ability to modulate pain pathways in vitro and in vivo warrants further investigation.

It is noteworthy that a wide array of plants and nutraceuticals are effectively utilized in the treatment of various cancers, demonstrating potent effects on different cancer targets with fewer side effects. Notably, estrogen alpha has been identified as a crucial factor in breast cancer cell proliferation. Agents that can antagonize its action hold promise as potential drug leads for the treatment of breast cancer. This study aims to discover and identify the potential inhibitors against the most influential ERα receptor by the computational approach of 134 phytochemicals from 17 medicinal plants by using in silico docking studies. The molecular docking was performed by a genetic algorithm using the Auto Dock Vina program, and the validation of docking was also performed by using Molecular Dynamic (MD) simulation by the Desmond tool of Schrödinger molecular modeling. Drug-likeness properties and toxicity studies were conducted using SWISS PRO. The top ten highest binding energy phytochemicals ginicidin (-10.8 kcal/mol), lemairone (-10.5 kcal/mol), ixoratannin (-10.0 kcal/mol), hydnocarpine (-9.8 kcal/mol), arabelline (-9.8 kcal/mol), acutilobine E (-9.8 kcal/mol), chaparinone (-8.9 kcal/mol), plumieride coumerate (-8.8 kcal/mol), acutilobine C (-8.7 kcal/mol), and mezerein (-8.7 kcal/mol) were taken for drug-likeness test and ADMET profile prediction with the help of web-based server SWISS ADME and protoxII. Docking's study dictated that ten phytochemical constituents showed greater binding interactions than standard tamoxifen (-6.6 kcal/mol) towards the target protein ERα. MSD study was achieved for the most active 4 phytoconstituents, and the stability of the ligand-protein complex was confirmed and showed that all the four compounds possess comparatively stable ligand-protein complexes with ERα target as compared to the tamoxifen-ERα complex. Among the top ten phytochemicals, ginicidin (glycoside) formed a more stable complex and had greater binding affinity than standard tamoxifen with better safety profiles. Hence, this compound can be further studied for lead optimization and drug development for the treatment of breast cancer.