YASARA Structure Research Articles

Anti-inflammatory potential of polyphenols: Combining in silico prediction and in vivo data

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation and destruction, leading to significant pain and disability. Adenosine deaminase (ADA) is identified as a biomarker for RA’s inflammatory process. This study aims to investigate the potential of flavonoids and phenolic acids to inhibit ADA activity (in silico) and evaluate their anti-inflammatory effects in a RA model (in vivo). Methods: The molecular docking study was conducted using YASARA Structure 19.12.14. software following the Auto Dock 4.2 protocol. A rat model with pristane-induced arthritis was used to test the anti-inflammatory effect of selected polyphenols. The consistency of the development of the rat model was evaluated through the following indicators artistic score, paw volume, and body weight. Quercetin was administered intragastrically at doses of 150 and 400 mg/kg over 15 days. The C-reactive protein (CRP) level in serum was measured with an automatic biochemical analyzer. Statistical analyses were performed using SPSS 29.0.2.0. Results: Molecular docking simulations showed flavonoids inhibited ADA activity with inhibition constants ranging from 0.012 mM to 0.190 mM. In the in vivo RA model, quercetin significantly reduced joint inflammation and serum CRP levels at a higher dose of 400 mg/kg. Conclusion: Quercetin shows promise as an anti-inflammatory agent for RA by targeting ADA, suggesting that flavonoid-rich plant extracts could enhance RA treatment.

Exploring the potential of Scabiosa columbaria in Alzheimer's disease treatment: An in silico approach

ObjectivesAlzheimer's disease (AD) is posing an increasing global threat and currently lacks effective treatments. Therefore, this study was aimed at exploring phytochemicals in Scabiosa columbaria (S. columbaria) as inhibitors of acetylcholinesterase (AChE), β-site APP cleavage enzyme 1 (BACE1), and TNF-α converting enzyme (TACE) in AD. S. columbaria contains various bioactive compounds, such as chlorogenic acid, linalool, and catechins, which are known for their detoxification properties, capacity to resist and manage harmful moisture buildup, and therapeutic roles in COVID-19. Several studies have also shown that S. columbaria extract has strong antioxidant activity, and may potentially decrease neuroinflammation in AD. Therefore, this study investigated the interactions between S. columbaria phytochemicals and key enzymes associated with AD, thus providing opportunities for the development of new therapeutic candidates. MethodsA total of 27 phytochemicals were evaluated for their inhibitory activity against AChE, BACE1, and TACE with YASARA Structure. ADMET profiles and toxicity were assessed. The top candidate compounds underwent 100 ns MD simulations. ResultsAll ligands met Lipinski's rule and showed low toxicity. Catechins, compared with the known drug galantamine, showed higher inhibitory activity and interacted with additional active sites on AChE, thus suggesting potentially higher efficacy. Moreover, chlorogenic acid showed stronger inhibitory activity against TACE than the control drug (aryl-sulfonamide), thereby suggesting a different mechanism of action. MD simulation revealed that the formed complexes had good stability. However, further exploration is necessary. ConclusionS. columbaria derivative compounds are promising drug candidates because of their properties, including the affinity of chlorogenic acid toward TACE and hydrogen bond enhancing ligand–receptor interactions. MD simulation indicated stable ligand–protein complexes, and the radius of gyration and MM-PBSA calculations revealed favorable binding and interaction energies. Our findings demonstrate the identified compounds' potential for further drug development.

Interactions Between Antimicrobial Peptides and Targets Responsible for their Nephrotoxic Action: Molecular Dynamics Simulations.

Polymyxin is the last line of defense against resistant forms of microorganisms, but it has significant nephrotoxicity. One of the directions in reducing the nephrotoxicity of polymyxin is to modify the charge of the molecule and accordingly, to change the topicity of the polymyxin derivative to the renal megalin. Such modification can lead to a decrease in the accumulation of polymyxin in the kidneys and reduce its toxicity while maintaining its antimicrobial properties. The study aimed to investigate the structural aspects of polymyxin nephrotoxicity at the atomic level to promote the more purposeful development of the polymyxin's derivatives with the lower nephrotoxic action. The molecular dynamics simulations of the complexes of polymyxin B and its derivative NAB7061 (that carries only three positive charges located within the macrocycle) with megalin were performed in program package YASARA structure with explicit water (TIP3P) and ions (0.9 % NaCl) in NPT ensemble using the AMRER03 force field. After 10 ns equilibration, each system was simulated at 298 K and pH 7.4 for a 25 ns production phase. Simulations were run twice for each molecular system. By molecular dynamics simulations, the possibility was shown for polymyxin to form a stable complex with two neighbor structural domains of megalin in accord with the universal mechanism of binding the cationic ligands by ligand-binding CR repeats of the LDLR-family receptors. It was reported that interactions of megalin with polymyxin were stronger than with its derivative having no positively charged groups outside the macrocycle. The structural prerequisites of these differences were revealed, explaining the less nephrotoxicity of such derivatives compared to polymyxin. Comparative molecular dynamics simulations of megalin interactions with polymyxin B and its derivative NAB7061, which carries no positive charges outside the macrocycle, revealed the possible structural prerequisites for the lower nephrotoxic action of such polymyxin derivatives. The weakening of polymyxins binding with megalin may become an effective preventive measure against polymyxin-induced nephrotoxicity.

Computational investigation of Y. aloifolia variegate as anti-Human Immunodeficiency Virus (HIV) targeting HIV-1 protease: A multiscale in-silico exploration

IntroductionHuman Immunodeficiency Virus (HIV) is a global challenge for the health sector due to the absence of a definitive cure. More than 38 million people are affected by the disease worldwide, with approximately 1.5 million new cases reported annually. This situation has spurred continued efforts in searching for drug candidates. Meanwhile, rutin, luteolin, and quercetin are compounds known for efficacy in treating infectious diseases. The compounds have also been detected in Yucca aloifolia (絲蘭) variegate L. Therefore, this study aimed to conduct a computational investigation utilizing multiscale in silico exploration to assess the potential of Y. aloifolia as an anti-HIV agent targeting HIV-1 Protease (H1P). MethodsFor the in silico study, the three-dimensional structure of H1P (PDB: 5V4Y) was retrieved and prepared using YASARA Structure. The binding pockets were identified using Cavity Plus server, and ligands were obtained from Y. aloifolia leaves alcohol extract. Furthermore, molecular docking was conducted with YASARA Structure to predict binding energies, followed by QSAR analysis for activity prediction. Density Functional Theory (DFT) analysis was performed to assess stability and reactivity, while toxicity was evaluated using ProTox 3.0. Molecular dynamics (MD) simulation and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculation were also conducted for further analysis. ResultsThe results showed that Ramachandran plot analysis indicated favorable residue distribution based on the evaluation of enzyme preparation quality. Cavity Plus identified potential binding sites, with cavity no.2 showing the highest druggability. Molecular docking showed rutin and isorhamnetin-3-O-rutinoside as top binders to H1P, with favorable binding energies. Moreover, post-docking analysis produced specific interactions between ligands and the receptor. PASS prediction indicated the potential of rutin and isorhamnetin-3-O-rutinoside (narcissin) as H1P inhibitors. DFT analysis assessed stability, showing comparable values for the investigated compounds. Toxicity analysis suggested both compounds to be non-toxic. Finally, MD simulation demonstrated the superior stability and binding affinity of rutin compared to isorhamnetin-3-O-rutinoside and the control drug, grl-09510. DiscussionRutin, hecogenin, and isorhamnetin-3-O-rutinoside from Y. aloifolia (絲蘭) leaves showed potential as H1P inhibitors through in silico study. Docking simulations indicated that rutin had the most favorable binding interactions, while MD simulation showed only the rutin-H1P complex to be stable, signifying the potential for further drug development. Rutin was identified as a promising lead for H1P inhibition due to its strong binding, stability, and predicted safety properties, underscoring the need for wet lab validation.

Molecular Docking and Dynamics of Xylocarpus granatum as A Potential Parkinson’s Drug Targeting Multiple Enzymes

Parkinson's disease is a global health challenge affecting over 10 million individuals worldwide, leading to increased disability-adjusted life years (DALYs) and a rise in mortality rates. This study explores the potential anti-Parkinson's properties of Xylocarpus granatum, focusing on its interaction with key enzymes associated with the disease: catechol-O-methyltransferase (COMT), adenosine A2A receptor (A2AR), and monoamine oxidase-B (MAO-B). Using molecular docking and molecular dynamics approaches with YASARA Structure, the ethanol extract of X. granatum was investigated for its mechanism of action. Among 30 compounds, five demonstrated promising binding affinities. Structural flexibility analysis revealed minimal fluctuations in active-site residues, highlighting the stability of key complexes involving kaempferol, epicatechin, epigallocatechin, and native ligands. Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) simulations provided insights into the binding energy of these complexes. Notably, kaempferol exhibited higher binding energy than the natural ligand, suggesting superior binding affinity. Analysis of the average radius of gyration (Rg) showcased control drug-MAO-B exhibited higher Rg values, indicating a more flexible protein conformation. Confirming mode stability with root mean square deviation (RMSD) analysis shows overall stability, except in the A2AR-bound complex. The study's collective findings underscore the structural stabilization of ligand-protein complexes, contributing valuable insights into the potential anti-Parkinson's properties of X. granatum. These discoveries hold promise for developing more effective therapies for Parkinson's disease and significantly contribute to the neurology field.

In silico study: molecular docking of SARS-Cov-2 endoribonuclease on active compounds of Gmelina arborea Roxb. bark

Infection by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) triggers COVID-19 disease of the respiratory tract similar to pneumonia. The virus encodes four structural proteins and 16 non-structural proteins (nsp), one of which includes nsp15 or endoribonuclease (NendoU). NendoU plays an important role in viral replication and transcription and reduces the stimulation of immune cell responses. Active compounds in Gmelina arborea Roxb. bark have antioxidant properties that can inhibit the NendoU activity of SARS-CoV-2. This study aims to analyze the potential of compounds from Gmelina arborea Roxb. bark in inhibiting SARS-CoV-2 NendoU within in silico using the YASARA structure application. Balnophonin is the best test ligand based on binding ΔG value, dissociation constant (Kd), prediction of physicochemical characteristics, pharmacokinetics, and toxicity. Therefore, balanophonin can be developed as an effective alternative drug to inhibit SARS CoV-2 NendoU.

In silico phylogenetic, physicochemical, and structural characteristics of phytase enzyme from ten Aspergillus species

Phytic acid is a chemical compound consisting of inositol and phosphoric acid and is an antinutrient compound found in monogastric poultry feed ingredients made from cereal crops. Phytase hydrolyzes phosphoester bonds in phytic acid, releasing inorganic phosphate and phosphate esters. Aspergillus is a genus of molds that produce phytase and has been widely used in phytase production because they are easy to culture. This study aims to compare the structures, physicochemical characteristics, and phylogenetic relationships of phytases from several species of Aspergillus in silico as an initial screening step in obtaining the most suitable phytase to be used in poultry feed. Phylogenetic trees were constructed using MEGA 11 and physicochemical characteristics were analyzed using ProtParam. Protein structures were modeled with AlphaFold. The phytase structures were then docked with phytic acid using the YASARA Structure. The results showed that phytase 1QFX from Aspergillus niger, P34755 from A. awamori, and D5HQ11 from A. ficuum have very high similarity in terms of phylogenetics, sequences, physicochemical characteristics, and protein structures. The docking results from the three phytase structures showed that phytase 1QFX has the most negative ΔG value and the lowest Kd, which indicated the highest affinity to the phytic acid substrate. This research concludes that among the three phytase structures that have been compared and docked with phytic acid, phytase 1QFX from A. niger is the most suitable to be applied to poultry feed.

Molecular Dynamics Simulation of Serotonin Transport Protein Complex with 6-Hydroxy-1-Methyl-1,2,3,4-Tetrahydro-β-Carboline Ligand from Chocolate (Theobroma cacao L.) Isolate

6-hydroxy-1-methyl1,2,3,4-tetrahydro-β-carboline (6OHMTHβC) is a chocolate derivate that has antidepressant potency. It can increase dopamine and serotonin secretion, which leads to mood improvement. This method was carried out using computational molecular docking simulations (in silico). The research design was computational-based exploratory descriptive. The results of molecular docking showed the lowest energy score and the backbone RMSD value ≤2Å. The procedure performed was 6AWP receptor docking without ligand, with native ligand (6OHMTHβC), and with reference ligand (fluvoxamine). This study also performed molecular docking simulations of 6OHMTHβC towards 6AWP to find compounds in the receptor binding pocket. This study also performed dynamics simulations and identified the molecular determinants using PyPLIF-HIPPOS and YASARA Structure software 20.1.24.10 with the Windows 10 operating system. This study succeeded in determining the stability of the dynamics simulation of the serotonin transport protein complex with the reference ligand 6OHMTHβC for 50 ns, and this result corresponds to the RMSD value and binding energy. The determination of binding energy (BE) was calculated from the BE calculation available at YASARA and Ubuntu. The binding energy value of the original ligand was -11.6590 kJ/mol, and the reference ligand was -83880 kJ/mol. The highest RMSD value of the original ligand was 1.39292Å, while the RMSD value of the reference ligand was 1.71072Å. The essential amino acid carried out was 438Ser with hydrogen bond interactions, so 6OHMTHβC was considered a competent antidepressant candidate.

Molecular Docking Study of Nigella sativa Alkaloid Compounds as the Inhibitor of Papain-Like Protease SARS-CoV-2

SARS-CoV-2 causes about 66% of China’s Wuhan market workers to experience fever, dry cough, and fatigue. Black cumin (Nigella sativa) is a plant with many benefits to cure many illnesses like hypertension, headache, infection, and inflammation. This study aimed to investigate the inhibition by compounds belonging to the Alkaloid group from Black Cumin Seed to inhibit PLpro activity as a target for SARS-CoV-2. The study used five alkaloid compounds ((2E,4E)-Decadienal, (2E,4Z)-Decadienal, Nigellicine, Nigellidine, and Nigellimine) from the Black cumin seed and a PLpro SARS-CoV-2 receptor (PDB ID: 6WX4). The methods used are ligand and receptor preparation, grid box validation, molecular docking, 2D and 3D visualisation, and data analysis using Gibbs free energy, type of interaction, and contact of amino acid residues data. This study used YASARA structure and BIOVIA Discovery Studio. The results showed that Nigellidine has the highest Gibbs free energy with a -2.67 kcal/mol score, higher than VIR251. PLpro has a catalytic triad at Cys111, His272, and Asp286 residues, the compound that binds to the active site is Nigellicine found at amino acid Cys111 with Pi-Sulfur.

Discovery of Mycobacterium tuberculosis CYP121 New Inhibitor via Structure-based Drug Repurposing

Tuberculosis (TB) remains a serious threat to human health with the advent of multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). The urge to find novel drugs to deal with the appearance of drug-resistant TB and its variants is highly needed. This study aims to find new CYP121 inhibitors by screening 8,773 compounds from the drug repositioning database RepoDB. The selection of CYP121 potential inhibitors was based on two criteria: the new inhibitor should bind to CYP121 with higher affinity than its original ligand and interact with catalytically important residues for the function of CYP121. The ligands were docked onto CYP121 using AutoDock Vina, and the molecular dynamics simulation of the selected ligand was conducted using YASARA Structure. We found that antrafenine, an anti-inflammatory and analgesic agent with high CYP inhibitory promiscuity, was bound to CYP121 with a binding affinity of -12.6 kcal/mol and interacted with important residues at the CYP121 binding site. Molecular dynamics analysis of CYP121 bound to the original ligand and antrafenine showed that both ligands affected the dynamics of residues located distantly from the active site. Antrafenine caused more structural changes to CYP121 than the original ligand, as indicated by a significantly higher number of affected residues and rigid body movements caused by the binding of antrafenine to CYP121.

Potential of Active Compounds in Leaves, Seeds, and Peel of Avocado Fruit (Persea americana Mill.) as In Silico Tyrosinase Enzyme Inhibitors

Melanocytes are an important component of skin pigmentation through their ability to produce melanin assisted by the enzyme tyrosinase which is a core enzyme in melanogenesis. The high phenolic and flavonoid compounds in the leaves, seeds and skin of avocados have potential as ligands (inhibitors) of tyrosinase related protein-1. This study aims to determine the active compounds from the leaves, seeds, and skin of avocados that play a role in inhibiting the activity of the tyrosinase enzyme in humans so that it can inhibit the formation of melanin. The research was conducted by molecular anchoring method using YASARA Structure software. The results showed that of the 68 active compounds of avocado leaves, seeds, and skins, there were 11 active compounds that had binding affinity for tyrosinase related protein-1, namely quarcetin, epicatechin, apigenin, 3-Hydroxytyrosol, scopoletin, abscisic acid, citric acid, coumaric acid. , quinic acid, vanillin, and caffeic acid. The active compound abscisic acid is the ligand with the best inhibitory potential with a bond free energy (∆G) of -2,645 kcal/mol which interacts with 17 amino acid residues. The research results can be used as a reference in in vitro and in vivo studies of the human tyrosinase enzyme.

Use of Cheminformatics to Determine Potential Drug Interactions between Popular Barbadian Botanical Medicines and Antihypertensive Drugs.

Barbados has a rich traditional use of medicinal plants, especially among the older population who may have a chronic noncommunicable disease. This study aims to identify possible drug-herb interactions between popular herbal remedies used to manage elevated blood pressure and conventional antihypertensive drugs. In this study, in silico molecular docking experiments with AutoDock Vina (Scripps Research Institute, La Jolla, CA), a part of Yasara Structure software, version 20.12.24, were used to screen 30 potential phytochemicals for drug interactions from 11 popular plants in Barbados that are used for high blood pressure and could influence the pharmacology of the most prescribed antihypertensive drugs in Barbados. Thiazide and thiazide-like diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACE-I), and angiotensin receptor blockers (ARBs) are the most prescribed antihypertensive drugs. Twenty-seven phytochemicals show dissociation constants (K d) < 10 μM with pharmacological drug targets. Catharanthus roseus (L.) G. Don, Phyllanthus niruri L., Petroselinum crispum (Mill.) Fuss, and Lantana involucrata L. contain various compounds that show high binding affinities in all experiments. Possible interactions could affect renal excretion (thiazide-like diuretics), CYP metabolism (CCBs), absorption (ACE-I), hepatic CYP, and phase II metabolism (ARB). Oleanolic acid shows high binding affinities to almost all protein targets. This study also reveals potential candidates for the drug targets: T-type Cav3.3 (psychiatric diseases), PEPT1/2 (influencing bioavailability), and BK channel (epilepsy). Twenty-seven of 30 phytochemicals from C. roseus (L.) G. Don (Madagascar periwinkle), P. niruri L. (Seed under leaf), P. crispum Mill. Fuss (Parsley), and L. involucrata L. (Rock sage) have potential binding affinities with pharmacological targets of frequently prescribed antihypertensive drugs in Barbados and are likely to cause drug interactions. Compounds that are similar to naringin (e.g., astragalin, rutin, and quercitrin) and compounds that bind to OATP1, PEPT1/2, and enzymes involved in the metabolism of CCBs may be clinically relevant for further research. There should be greater awareness of potential drug-herb interactions, and further in vitro and in vivo studies are needed to unravel the exact effects on the pharmacology.

Selected Polyphenols from Date (Phoenix dactylifera) as Anti-Virulence of Candida albicans Through Multiple Enzyme Targets

Candida albicans (C. albicans) have long been attributed to various diseases like candidiasis and systemic diseases and exacerbate the symptoms of immunocompromised patients. C. albicans has enzymes that could function as drug targets to decrease its pathogenicity and eradicate the fungi. This research aimed to investigate the potency of selected polyphenols contained in dates (Phoenix dactylifera) in inhibiting important enzymes of C. albicans through molecular docking simulation. The structures of four target enzymes (Sap 1, Sap 2, Sap 3, Sap 5) of C. albicans and six selected polyphenol compounds from dates were downloaded from PDB and prepared using YASARA Structure. A molecular docking simulation was conducted using YASARA Structure. Docking results showed that procyanidin has a high binding affinity with target protein Sap 1 and Sap 5, while beta carotene has a high binding affinity with Sap 2 and Sap 3. The binding affinity range of all ligand-receptor complexes was as follows: Sap 1 (5.782 – 9.907 kcal/mol), Sap 2 (5.943 – 9.343 kcal/mol), Sap 3 (5.732 – 8.905 kcal/mol), and Sap 5 (5.873 – 9.430 kcal/mol). The interactions formed included hydrogen bonding, electrostatic and hydrophobic interactions, and unfavorable bindings. The data generated from molecular docking analysis warrant further experiments are necessary.

In depth molecular interaction analyses of the complex of a proposed CTXM-inhibitor bound to the bacterial enzyme

A ‘Thumb Rule for Antibiotic Design’ against bacteria can be given as, ‘The minimum pace of drug design ought to match the swiftness with which bacteria display cutting-edge resistance mechanisms; thereby outwitting the antibiotics and, in turn, the researchers’. Occurrence of drug resistance attributable to CXTM-variants in bacterial pathogens is widespread. In line with our above proposed thumb rule, the present article employed concatenation of virtual screening, docking and simulation to identify a potent in silico validated anti-CTXM-14 ligand. Specifically, this research used the ‘MCULE’ drug discovery platform to screen a total of 5 million candidate inhibitors to evaluate their binding efficacy with an antibiotic resistance enzyme, CTXM-14 found in bacterial pathogens. A new median approach between ‘structure’ and ‘ligand’-based protocols was employed. Pharmacokinetic profiling was achieved by ‘SWISS ADME’. Safety profile for humans was appraised by ‘Toxicity Checker’. The complex consisting of the ‘Top ligand’ (obtained from the screen) harbored within the active pocket of the bacterial CTXM-14 was subjected to 60 ns molecular dynamics simulation with the aid of licensed YASARA STRUCTURE v.21.8.27. Complex tasks were performed by YANACONDA. Fine resolution figures (notably, plots generated from trajectory analyses) were constructed. Simulation snaps were acquired at every 250 picoseconds of the run. The ligand having the IUPAC name as 1-Amino-3-(4-hydroxyphenyl)pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile demonstrated the overall best binding with CTXM-14. Fifteen amino acid residues were found to line the interacting pocket. Remarkably, all of these interacting residues were found to be present among the interacting residues displayed by the reference complex as well, i.e. CTXM-14:Vaborbactam complex (PDB ID 6V7H). A total of 240 simulation snaps were retrieved. The RMSD plot revealed that a plateau was achieved at 32 ns, after which the backbone RMSD fluctuations remained confined within 1.4-2 Å. Video recording of molecular actions was also achieved. In conclusion, this study provides a fresh lead molecule, 1-Amino-3-(4-hydroxyphenyl)pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile against bacterial CTXM-14 protein. The study utilized a new median approach between ‘structure’ and ‘ligand’-based drug design. The lead molecule passed ADMET conditions and an array of medicinal chemistry filters, and is further supported by a stable molecular dynamics. An acceptable skin permeation supports its probable use in antibiotic creams. Moreover, the study provides a clear ‘Thumb Rule for Antibiotic Design’ against bacteria, which although often assumed, can be clearly stated for the first time. Synthesis of the screening-proposed molecule followed by in-vitro and in-vivo validation is highly recommended. Communicated by Ramaswamy H. Sarma

Molecular docking study of natural compounds from red betel (Piper crocatum Ruiz &amp; Pav) as inhibitor of secreted aspartic proteinase 5 (Sap 5) in Candida albicans

Candida albicans can cause adverse infections in humans. The targeting of Sap 5 is due to its virulence factor in C. albicans. The method used is molecular docking using YASARA structure and BIOVIA Discovery Studio. The purpose of this study was to investigate the molecular interaction between red betel and Sap 5 as a potential inhibitor of C. albicans in infecting humans. The results showed that CHEMBL216163 (9,644 kcal/mol) and MLS000557666 (9,525 kcal/mol) have Binding energy above Pepstatin (9,484 kcal/mol) and affect the active site of Sap 5 so that the two test ligands could be further analyzed.

Dithymoquinone Analogues as Potential Candidate(s) for Neurological Manifestation Associated with COVID-19: A Therapeutic Strategy for Neuro-COVID.

The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CLpro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CLpro, TLR4 and PREP with a binding energy of −8.5 kcal/mol, −10.8 kcal/mol and −9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski’s rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.

Oleuropein as a Potent Compound against Neurological Complications Linked with COVID-19: A Computational Biology Approach.

The association of COVID-19 with neurological complications is a well-known fact, and researchers are endeavoring to investigate the mechanistic perspectives behind it. SARS-CoV-2 can bind to Toll-like receptor 4 (TLR-4) that would eventually lead to α-synuclein aggregation in neurons and stimulation of neurodegeneration pathways. Olive leaves have been reported as a promising phytotherapy or co-therapy against COVID-19, and oleuropein is one of the major active components of olive leaves. In the current study, oleuropein was investigated against SARS-CoV-2 target (main protease 3CLpro), TLR-4 and Prolyl Oligopeptidases (POP), to explore oleuropein potency against the neurological complications associated with COVID-19. Docking experiments, docking validation, interaction analysis, and molecular dynamic simulation analysis were performed to provide insight into the binding pattern of oleuropein with the three target proteins. Interaction analysis revealed strong bonding between oleuropein and the active site amino acid residues of the target proteins. Results were further compared with positive control lopinavir (3CLpro), resatorvid (TLR-4), and berberine (POP). Moreover, molecular dynamic simulation was performed using YASARA structure tool, and AMBER14 force field was applied to examine an 100 ns trajectory run. For each target protein-oleuropein complex, RMSD, RoG, and total potential energy were estimated, and 400 snapshots were obtained after each 250 ps. Docking analyses showed binding energy as −7.8, −8.3, and −8.5 kcal/mol for oleuropein-3CLpro, oleuropein-TLR4, and oleuropein-POP interactions, respectively. Importantly, target protein-oleuropein complexes were stable during the 100 ns simulation run. However, an experimental in vitro study of the binding of oleuropein to the purified targets would be necessary to confirm the present study outcomes.

Potency of Bioactive Compounds in Indramayu Mango Peel Waste to Inhibit ACE2

According to reports, mango peel contains bioactive compounds—especially phenolic—threefold higher than the flesh. This issue underlies the research that aims to identify bioactive compounds from Indramayu mango peel which have the potential as ACE2 inhibitors. The study was initiated by extracting mango peel simplicia using aquadest, then carried out with phytochemical screening, and identification of compound content by LC-MS. The extraction obtained 21.3% of yield. The results of phytochemical screening showed that secondary metabolites in the form of alkaloids, flavonoids, saponins, and tannins were identified in the mango peel. At the same time, the LC-MS fragmentation results obtained 40 compounds based on the largest sample area. The result from fragmentation were tested for Lipinski bioavailability prediction and ADMET test and obtained 10 potential compounds. Molecular docking was performed on the ACE2 receptor with 10 sample ligands and 1 comparison ligand using YASARA Structure. All of the sample ligands (from Lipinski and ADMET test) showed higher free energies than comparison ligand, chloroquine. Mangiferin is a typical mango compound identified in LC-MS, had inhibitor activity against ACE2. Two-dimensional visualization using Discovery Studio showed mangiferin interaction with the receptor via hydrogen bond, hydrogen carbon bond and phi-anion interactions at three amino acid residues (Thr371, Glu375, Glu402) on the active site of ACE2.&#x0D; Keywords: ACE2, bioactive compound, mango peel, mangiferin, waste

Molecular interaction of inhibitors with human brain butyrylcholinesterase.

Alzheimer's disease is a topic of deep research interest across the global scientific community. Butyrylcholinesterase (BuChE) is an important enzyme, and an interesting anti-Alzheimer's target. Identification or fresh design of promising BuChE-inhibitors is warranted. Virtual screening supported by molecular dynamics simulations has emerged as a key component of present drug-discovery cascades. The research piece aimed at identification of a putative BuChE-inhibitor as a fresh molecular frame that might aid drug design in the context of Alzheimer's disease. The study utilized 'MCULE' to screen a set of 5 million ligands to test their ability to bind to human BuChE. Pharmacokinetic profiling was achieved by the 'SWISS ADME' program. Toxicities were duly assessed. YASARA STRUCTURE version 20.10.4.W.64 was employed to run 133 ns molecular dynamics (MD) simulation for the complex of 'the top screened out inhibitor' and 'the human BuChE enzyme'. The simulation was executed for approx. 4 days (~93 hrs) on an HP ZR30w workstation. YANACONDA, a special language contained in YASARA STRUCTURE was employed to perform complex tasks. Fine resolution figures (notably the RMSD vs time plot) were created. Snapshots were extracted at every 250 ps. The selected ligand, (3-Bromophenyl)[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl]methanone, exhibited the best overall binding with human BuChE. It interacted with human BuChE through 19 residues. Markedly, 9 of the 19 residues were confirmed to be matching to those of the reference complex (PDB ID 5DYW). Trajectory analysis returned 533 snapshots. The RMSD versus time plot indicated that around 22 ns, equilibrium was achieved and, from then on, the 'BuChE-Top inhibitor' complex remained predominantly stable. From 22 ns and onwards till 133 ns, the backbone RMSD fluctuations were observed to remain limited within a range of 1.2-1.9 Å. The molecule, (3-Bromophenyl)[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl]methanone, satisfied ADMET requirements. Additionally, the feasibility of the proposed enzyme-inhibitor complex was supported by an adequately extended MD simulation of 133 ns. Hence, the proposed molecule could be a likely lead for designing inhibitor(s) against human BuChE. Scope remains for validatory wet laboratory investigation.

Identifying the Most Potent Dual-Targeting Compound(s) against 3CLprotease and NSP15exonuclease of SARS-CoV-2 from Nigella sativa: Virtual Screening via Physicochemical Properties, Docking and Dynamic Simulation Analysis

Background: The outbreak of the coronavirus (SARS-CoV-2) has drastically affected the human population and caused enormous economic deprivation. It belongs to the β-coronavirus family and causes various problems such as acute respiratory distress syndrome and has resulted in a global pandemic. Though various medications have been under trial for combating COVID-19, specific medicine for treating COVID-19 is unavailable. Thus, the current situation urgently requires effective treatment modalities. Nigella sativa, a natural herb with reported antiviral activity and various pharmacological properties, has been selected in the present study to identify a therapeutic possibility for treating COVID-19. Methods: The present work aimed to virtually screen the bioactive compounds of N. sativa based on the physicochemical properties and docking approach against two SARS-CoV-2 enzymes responsible for crucial functions: 3CLpro (Main protease) and NSP15 (Nonstructural protein 15 or exonuclease). However, simulation trajectory analyses for 100 ns were accomplished by using the YASARA STRUCTURE tool based on the AMBER14 force field with 400 snapshots every 250 ps. RMSD and RMSF plots were successfully obtained for each target. Results: The results of molecular docking have shown higher binding energy of dithymoquinone (DTQ), a compound of N. sativa against 3CLpro and Nsp15, i.e., −8.56 kcal/mol and −8.31 kcal/mol, respectively. Further, the dynamic simulation has shown good stability of DTQ against both the targeted enzymes. In addition, physicochemical evaluation and toxicity assessment also revealed that DTQ obeyed the Lipinski rule and did not have any toxic side effects. Importantly, DTQ was much better in every aspect among the 13 N. sativa compounds and 2 control compounds tested. Conclusions: The results predicted that DTQ is a potent therapeutic molecule that could dual-target both 3CLpro and NSP15 for anti-COVID therapy.