Virtual prediction of purple rice ferulic acid as anti-inflammatory of TNF-α signaling

Purple rice is one of the main sources of ferulic acid (FA). Some studies reported anti-inflammatory properties of FA, but the interaction of FA with TNF-α signaling has not been elucidated. TNF-α is a target for anti-inflammatory drug research due to its major role in the inflammatory process. This study aims to investigate the interaction of FA with TNF-α and TNF-α receptor (TNFR) through in silico study and evaluate the drug-like properties and biological activity of FA. The interactions among FA (CID 445858), TNF-α (2AZ5), and TNFR (1NCF) were docked by Hex 8.0.0 Cuda, then visualized by Discovery Studio 2020 and LigPlot V.1.4.5. Apigenin-7-glucuronide (AG, CID 5319484) was used as the positive control. The drug-like properties were predicted by Lipinski’s rule of five and the biological activity was analyzed by PASS online. FA showed good properties as a drug-like molecule and biological activity as an anti-inflammatory. FA also showed good interaction with TNF-α and TNFR. FA bound to TNF-α at Asn92(B), Val91(B), Leu93(B), Phe124(B), Phe124(D), and Leu93(D) residues with docking energy of -214.6 kJ/mol, and bound to TNFR at Pro16(A), Glu56(B), Cys55(B), Glu54(B) residues with docking energy of -191.1 kJ/mol. FA could inhibit TNF-α – TNFR interaction by binding to TNFR at Glu54 residue, the same inhibition mechanism to AG which bind to TNFR at Glu54 and Val90. The current study shows that FA has the potential as an anti-inflammatory of TNF-α signaling and can be developed as an oral anti-inflammatory drug candidate.

Computational Screening of Isolated Compounds From Goniothalamus Species to Identify Potential Inhibitors for Dengue Virus

In this study, a set of 234 chemical constituents reported from Goniothalamus species were docked against envelope (E), NS2B/NS3, NS5 methyltransferase, and NS5 RdRp dengue virus (DENV) protein. As the result, compounds 95, 96, 97, 100, 149, 155, and 187 were identified as potential dengue protease inhibitors based on minimal docking energy values and multiple interactions with binding sites. The results from in-silico Lipinski’ rule and ADMET analysis showed that compound 149 was predicted as the most potential compound that fulfills the drug-likeness properties. Ligand 149 was found to be able to fit in well and remain stable in the binding site of proteins envelope, NS2B/NS3, NS5 methyltransferase and NS5 RdRp. The results from molecular dynamic simulations indicate that the ligand-protein complex of 149 in NS5 methyltransferase showed the most preferable, successfully interacted within the active sites and were able to reach convergence within 100 ns.

In silico Approach to Identify Potent Bioactive Compounds as Inhibitors against the Enoyl-acyl Carrier Protein (acp) Reductase Enzyme of Mycobacterium tuberculosis

The enoyl-acyl carrier protein (ACP) reductase (InhA) of Mycobacterium tuberculosis elongates acyl fatty acids, which are progenitors of mycolic acids and that are mycobacterial cell wall parts. The aim is to discover potent therapeutic novel bioactive compounds as enoyl-acyl carrier protein (ACP) reductase (InhA, PDB ID: 4U0J) antagonists using an in silico drug design scheme. Structure-based computerized prediction of drug-receptor interactions. PyRx virtual screening tool was used to conduct molecular docking investigations on enoyl-ACP reductase. A target-based ligand selection strategy to choose ligand compounds was employed. The ligand structure was chosen using LEA3D-CNRS. Medication data set that was approved by the FDA: 2028 molecule (s) were used in the study. Around 27 bioactive molecules can bind to the 4U0J, with docking scores ranging from -6.2 to -11.2 Kcal/mol. Compound CHEMBL441373 was shown to have the highest acceptable docking energy (-11.1Kcal/mol), making it a good candidate for a cell wall protein inhibitor (4U0J) that should be investigated further in vivo and in vitro. The anti-mycobacterial ability of triazole scaffolding in a new therapeutic was determined. Compound CHEMBL441373 is located to possess high docking energy (-11.1Kcal/mol) and is shown as a suitable molecule of cell wall protein inhibitor (4U0J).

Discovery of Potential Anti-Ischemic Stroke Agents Through Inhibiting Sulfonylurea Receptor 1 (SUR1): A Pharmacophore-based Screening, Docking, and Molecular Dynamic Simulation

Stroke is the leading cause of disability and death worldwide. Inhibition of sulfonylurea 1 receptor (SUR1) using glibenclamide previously has been studied in CNS ischemic tissues and faster recovery from stroke injury in different animal models of stroke. Unfortunately, glibenclamide cannot enter the brain through an intact brain membrane (BBB) due to its ionization at physiological pH. Therefore, it was hypothesized that compounds with structural properties similar to glibenclamide but with the ability to penetrate through BBB would be superior to glibenclamide in ischemic stroke. Docking energy and interactions of glibenclamide with SUR1 active site were assessed using AutoDock Vina. NCI databases search engines with limitations for penetration to CNS were used to find the best compounds with desired properties. Then two selected compounds were assessed with dynamic molecular studies. Two compounds called CID-415537 and CID-419074 with docking energies of -10.3 kcal/mol and -11 kcal/mol were identified. CID-415537 was selected as the best compound due to its proper interactions with SUR1 amino acids and stability in molecular dynamic simulation. Based on this study, compound CID-415537 would be a good candidate for a SUR1 inhibitor in ischemic stroke. However, further in vivo investigations are required to confirm these findings.

Subtractive Proteomics Analysis Revealed Lipid A-4’phosphatase (lpxF) as a Potential Candidate for Epitope-based Vaccine Design Against Helicobacter pylori Infection

Amidst the surge in the prevalence of resistant H. pylori infections, WHO in 2017 has given a high priority to clarithromycin-resistant H. pylori for research and to develop new antibacterial agents. In this study, the Helicobacter pylori 26695 strain was investigated with extensive computational biology applications to identify novel therapeutic drug targets or vaccine candidates. During the proteomic functional annotation of an organism, it is crucial to determine the function of proteins. The pathogen-specific pathways were found to include only twelve proteins, paving the way further to determine drug or vaccine targets. Lipoprotein A-4’-phosphatase (LpxF) was found to be a novel vaccine target with the highest antigenicity. Having broad-spectrum conservancy with other H. pylori strains. Further, an immunoinformatic approach was used to predict an effective epitope-based vaccine against H. pylori. LpxF protein has been predicted to have linear and conformational B-cell epitopes and cytotoxic T-lymphocyte epitopes. Virtual screening of all the predicted 35 peptides against human TLR2 receptors resulted in identifying the top 5 peptides. Subsequent redocking with exhaustive parameters reported two peptides with docking energy of -6.9 kcal/mol with a good interaction pattern between the peptide-TLR2 complexes. Furthermore, a panel of two potent epitopes has been proposed that could be used to immunize populations against multiple H. pylori infections.

Determination of Hybrid TSPO Ligands with Minimal Impact of SNP (rs6971) through Molecular Docking and MD Simulation Study

Background: In an endeavor to ascertain high affinity TSPO ligands with minimal single nucleotide polymorphism (SNP), six hybrid molecules have been identified as new leads for future inflammation PET imaging. Objective: Genesis for chemical design was encouraged from structural families of well-known ligands FEBMP and PBR28/ DAA1106 that has demonstrated remarkable TSPO binding characteristics. Methods: All proposed hybrid ligands 1-6 are subjected to molecular docking and simulation studies with wild and mutant protein to study their interactions, binding, consistency of active conformations and are correlated with well-established TSPO ligands. Results: Each hybrid ligand demonstrate better docking score > -11.00 kcal/mol with TSPO with respect to gold standard PK11195 i.e., -11.00 kcal/mol for 4UC3 and -12.94 kcal/mol for 4UC1. On comparison with FEBMP and GE-180 (-12.57,-7.24 kcal/mol for 4UC3 and -14.10,-11.32 kcal/mol for 4UC1), ligand 3 demonstrate maximum docking energy (>-15.50 kcal/mol), minimum SNP (0.26 kcal/mol). Discussion: Presence of strong hydrogen bond Arg148-3.27Å (4UC1) and Trp50-2.43Å, Asp28-2.57Å (4UC3) apart from short-range interactions including π–π interactions with the aromatic residues such as (Trp39, Phe46, Trp135) and (Trp39, Trp108) that attributes towards its strong binding. Conclusion: Utilizing the results of binding energy, we concluded stable complex formation of these hybrid ligands that could bind to TSPO with least effect of SNP with similar interactions to known ligands. Overall ligand 3 stand out as the best ligand having insignificant deviations per residue of protein that can be further explored and assessed in detail for future inflammation PET application after subsequent detailed biological evaluation.

N,N’-Dialkyl-2-Thiobarbituric acid based Sulfonamides as potential SARS-CoV-2 main protease inhibitors

An efficient methodology was developed to avail novel N,N’-dialkyl-2-thiobarbituric acid based sulfonamides S1-S4 in good to excellent yields (84-95%). The synthesized compounds S1-S4 were docked to screen their In-silico activities against two enzymes i.e. SARS-CoV-2 main protease enzyme with unliganded active site (2019-nCoV, coronavirus disease 2019, COVID-19) PDB ID: 6Y84 and SARS-CoV-2 Mpro PDB ID: 6LU7. Furthermore, some In-silico physicochemical and physicokinetic properties were evaluated using OSIRIS property explorer online, molinspiration property calculator, ADMET property calculator and GUSAR to assess these compounds as potential candidates as lead compounds for the quest of SARS- CoV-2 main protease inhibitors. Molecular docking analyses of the synthesized compounds predicted that compound S3 is more potent as SARS-CoV-2 main protease inhibitor with binding energy -11.65 Kcal/mol in comparison to reference inhibitor N3 (-10.95 Kcal/mol), whereas, compounds S1, S2 and S4 recorded comparable binding energies -9.89 Kcal/mol, -10.84 Kcal/mol and -10.94 Kcal/mol with reference inhibitor N3, however much better than remdesivir (-9.85 Kcal/mol). In case of SARS-CoV-2 Mpro, all compounds S1-S4 with docking energy values as -7.28, -8.38, -8.31 and -7.34 Kcal/mol were found potent in comparison to reference inhibitor N3 (-6.31 Kcal/mol) as well as remdesivir (-6.33 Kcal/mol). Ligand efficiency values against the target SARS-CoV-2 proteins as well as α-glucosidase and DNA-(apurinic or apyrimidinic site) lyase inhibition results of these newly synthesized compounds were also found promising.

Cannabis sativa L. chemical compositions as potential plasmodium falciparum dihydrofolate reductase-thymidinesynthase enzyme inhibitors: An in silico study for drug development

This study contributes to anti-malarial research effort by conducting in silico assessment of 125 compounds originated from Cannabis sativa L. against plasmodium falciparum dihydrofolate reductase-thymidinesynthase (pfDHFR-TS) enzyme for potential inhibition activity. Drug-like and pharmacokinetic criteria were used to assess the drug-like properties of the studied compounds. AutoDock4.2.6 and AutoDock Vina software were used to calculate the possible binding pose of the studied compounds to pfDHFR-TS enzyme. The docking procedure was validated using two known inhibitors cycloguanil and WR99210. 65 out of 125 compounds violated no more than 2 of Lipinski’s rule of five and were sorted out as favorable for drug development. Amongst these 65 compounds, pharmacokinetic properties and toxicity evaluation identified 60 compounds that meet the criteria of drug-like properties and were subjected to further docking studies. Docking outcomes identified 10 compounds including compounds 4, 9, 19, 22, 23, 25, 30, 42, 43, and 59 as potential candidates for inhibiting the function of pfDHFR-TS at the active site through hydrogen bonds with Ile14, Asp54, and Ile 164 residues. Compound 9 is considered as the top “hit” with docking energy far more exceeding those of the standard compounds. High correlation coefficient between the docking energy of AutoDock4.2.6 and AutoDock Vina was recorded with the value of R 2 = 0.74.

Molecular Docking and Dynamics Simulation Analysis of Thymoquinone and Thymol Compounds from Nigella sativa L. that Inhibit Cag A and Vac A Oncoprotein of Helicobacter pylori: Probable Treatment of H. pylori Infections

Background: Helicobacter pylori infection is accountable for most of the peptic ulcer and intestinal cancers. Due to the uprising resistance towards H. pylori infection through the present and common proton pump inhibitors regimens, the investigation of novel candidates is the inevitable issue. Medicinal plants have always been a source of lead compounds for drug discovery. The research of the related effective enzymes linked with this gram-negative bacterium is critical for the discovery of novel drug targets. Objective: The aim of the study is to identify the best candidate to evaluate the inhibitory effect of thymoquinone and thymol against H. pylori oncoproteins, Cag A and Vac A in comparison to the standard drug, metronidazole by using a computational approach. Materials and Methods: The targeted oncoproteins, Cag A and Vac A were retrieved from RCSB PDB. Lipinski’s rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa. The two compounds of N. sativa were further analyzed by molecular docking and MD simulation studies. The reported phytoconstituents, thymoquinone and thymol present in N. sativa were docked with H. pylori Cag A and Vac A oncoproteins. Structures of ligands were prepared using ChemDraw Ultra 10 software and then changed into their 3D PDB structures using Molinspiration followed by energy minimization by using software Discovery Studio client 2.5. Results: The docking results revealed the promising inhibitory potential of thymoquinone against Cag A and Vac A with docking energy of -5.81 kcal/mole and -3.61kcal/mole, respectively. On the contrary, the inhibitory potential of thymol against Cag A and Vac A in terms of docking energy was -5.37 kcal/mole and -3.94kcal/mole as compared to the standard drug, metronidazole having docking energy of -4.87 kcal/mole and -3.20 kcal/mole, respectively. Further, molecular dynamic simulations were conducted for 5ns for optimization, flexibility prediction, and determination of folded Cag A and Vac A oncoproteins stability. The Cag A and Vac A oncoproteins-TQ complexes were found to be quite stable with the root mean square deviation value of 0.2nm. Conclusion: The computational approaches suggested that thymoquinone and thymol may play an effective pharmacological role to treat H. pylori infection. Hence, it could be summarized that the ligands thymoquinone and thymol bound and interacted well with the proteins Cag A and Vac A as compared to the ligand MTZ. Our study showed that all lead compounds had good interaction with Cag A and Vac A proteins and suggested them to be a useful target to inhibit H. pylori infection.

New Putative Antimicrobial Candidates: In silico Design of Fish-Derived Antibacterial Peptide-Motifs

Antimicrobial resistance remains a great threat to global health. In response to the World Health Organizations’ global call for action, nature has been explored for novel and safe antimicrobial candidates. To date, fish have gained recognition as potential source of safe, broad spectrum and effective antimicrobial therapeutics. The use of computational methods to design antimicrobial candidates of industrial application has however, been lagging behind. To fill the gap and contribute to the current fish-derived antimicrobial peptide repertoire, this study used Support Vector Machines algorithm to fish out fish-antimicrobial peptide-motif candidates encrypted in 127 peptides submitted at the Antimicrobial Peptide Database (APD3), steered by their physico-chemical characteristics (i.e., positive net charge, hydrophobicity, stability, molecular weight and sequence length). The best two novel antimicrobial peptide-motifs (A15_B, A15_E) with the lowest instability index (−28.25, −22.49, respectively) and highest isoelectric point (pI) index (10.48 for each) were selected for further analysis. Their 3D structures were predicted using I-TASSER and PEP-FOLD servers while ProSA, PROCHECK, and ANOLEA were used to validate them. The models predicted by I-TASSER were found to be better than those predicted by PEP-FOLD upon validation. Two I-TASSER models with the lowest c-score of −0.10 and −0.30 for A15_B and A15_E peptide-motifs, respectively, were selected for docking against known bacterial-antimicrobial target-proteins retrieved from protein databank (PDB). Carbapenam-3-carboxylate synthase (PDB ID; 4oj8) yielded the lowest docking energy (−8.80 and −7.80 Kcal/mol) against motif A15_B and A15_E, respectively, using AutoDock VINA. Further, in addition to Carbapenam-3-carboxylate synthase, these peptides (A15_B and A15_E) were found to as well bind to membrane protein (PDB ID: 1by3) and Carbapenem synthetase (PDB: 1q15) when ClusPro and HPEPDOCK tools were used. The membrane protein yielded docking energy scores (DES): −290.094, −270.751; coefficient weight (CW): −763.6, 763.3 for A15_B and A15_E) whereas, Carbapenem synthetase (PDB: 1q15) had a DES of −236.802, −262.75 and a CW of −819.7, −829.7 for peptides A15_B and A15_E, respectively. Motif A15_B of amino acid positions 2–19 in Pleurocidin exhibited the strongest in silico antimicrobial potentials. This segment could be a good biological candidate of great application in pharmaceutical industries as an antimicrobial drug candidate.