Application Of Molecular Docking Research Articles

Design, spectroscopic characterization, DFT, molecular docking, and different applications: Anti-corrosion and antioxidant of novel metal complexes derived from ofloxacin-based Schiff base

A new tridentate Schiff base ligand derived from ofloxacin (oflo) with 2-aminophenol was synthesized and a series of d-transition metal complexes were prepared. The ligand and its metal complexes were investigated using elemental, spectral, and thermal studies. The molecular and electronic structure of the free ligand and its Zn(II) complex were refined theoretically, and the chemical quantum parameters were computed. SEM studies were conducted on the free ligand and its Ni(II) chelate to confirm their nanostructure. The anti-corrosive performance of HL for mild steel (MS) was employed using electrochemical frequency modulation (EFM), potentiodynamic polarization (PP) and electrochemical impedance spectroscopy (EIS) and showed a significant efficiency as anticorrosion agent (89.71%). Molecular docking studies were carried out between the ligand and its [Zn(HL)(H2O)Cl2] complex with active sites of 3T88, 3Q8U, and 3Q7K receptors and the complex showed the strongest binding with 3T88 receptor (-31.9 kcal mol−1). The antioxidant activity of the free ligand and its metal chelates had been carried out using the standard DPPH method and the free ligand showed the highest antioxidant activity (IC50 = 10.52 µg/mL). The in vitro antibacterial activity showed that all prepared compounds were biologically active and Fe(III) complex has the highest inhibiting activity against Proteus Vulgaris Gram-negative bacteria.

DNA protection, molecular docking, antioxidant, antibacterial, enzyme inhibition, and enzyme kinetic studies for parietin, isolated from Xanthoria parietina (L.) Th. Fr.

Parietin was isolated from Xanthoria parietina (L.) Th. Fr.’ (methanol:chloroform) extract, using a silica column. 13 C NMR and 1H NMR were used to confirm the structure of the isolated parietin. For the first time, parietin was investigated for its antioxidant, antibacterial and DNA protective activities. Molecular docking was carried out to determine the binding affinity and interactions between the enzymes and our molecule. Inhibition and kinetic mechanism studies for the action of the enzymes were performed too. Parietin exhibited high metal chelating activity. The MIC values of parietin were sufficient to inhibit different bacterial strains; E. coli, P. aeruginosa, K. pneumoniae and S. aureus. Molecular docking applications exhibited that acetylcholinesterase (AChE), butyrylcholinesterase (BChE), lipase, and tyrosinase have high potential for binding with the parietin. Especially, the parietin’s highest binding affinity was recorded with AChE and tyrosinase. These results were confirmed by the inhibition and kinetics results, where, parietin observed a potent inhibition with an IC50 values between 0.013-0.003 µM. Moreover, parietin acts’ as a non-competitive inhibitor against AChE, BChE, and lipase, and as a competitive inhibitor against tyrosinase with a high rate of inhibition stability. The promising biological properties of parietin revealed its effectiveness in terms of suitability in the food and pharmaceutical industries. Communicated by Ramaswamy H. Sarma

HPLC-DAD technique for the quantification of a recently approved anti-diabetic triple combination along with two toxic official impurities: Toxicity confirmation aided by molecular docking application

BackgroundGliflozins and gliptins are two distinct groups of pharmacological drugs that reduce blood glucose levels in individuals with type II diabetes in various ways that may perform their functions harmoniously. Trijardy® tablet, which contains empagliflozin, linagliptin, and metformin, was recently approved. The scientific database does not yet have a method that is sensitive enough to quantify the aforementioned medications in the presence of metformin official toxic impurities melamine and cyanoguanidine. Molecular docking modeling was utilized in this work to further prove the toxicity of melamine.MethodsThe five analytes listed before were quantified using RP-HPLC-diode array detector and a Zorbax® C8 column (4.6 × 250 mm, 5 μm) with isocratic mobile phase composed of acetonitrile and 0.05 M potassium dihydrogen phosphate buffer, which had been treated by ?-phosphoric acid to restore a pH of 4.0 (90:10, v/v) at a flow rate of 1.2 mL/min and the eluted peaks were scanned at 250 nm.ConclusionThe utilization of the simplest isocratic elution mode give the current technique a significant time-and cost-saving benefit. The current method can quantify the triple therapy agents in the presence of each other as well as with two official toxic impurities of metformin in one short analytical run.

Panoramic Review on Progress and Development of Molecular Docking

In structural molecular biology and computer-assisted drug creation, molecular docking is a crucial tool. Predicting the prevailing binding mode (s) of a ligand with a protein having a known three-dimensional structure is the aim of ligand-protein docking. Effective docking methods use a scoring system that correctly ranks candidate dockings and efficiently explore high-dimensional spaces. Lead optimization benefits greatly from the use of docking to do virtual screening on huge libraries of compounds, rate the outcomes, and offer structural ideas for how the ligands inhibit the target. It can be difficult to interpret the findings of stochastic search methods, and setting up the input structures for docking is just as crucial as docking itself. In recent years, computer-assisted drug design has relied heavily on the molecular docking technique to estimate the binding affinity and assess the interactive mode since it can significantly increase efficiency and lower research costs. The main concepts, techniques, and frequently utilized molecular docking applications are introduced in this work. Additionally, it contrasts the most popular docking applications and suggests relevant study fields. Finally, a brief summary of recent developments in molecular docking, including the integrated technique and deep learning, is provided. Current docking applications are not precise enough to forecast the binding affinity due to the insufficient molecular structure and the inadequacies of the scoring mechanism.

Molecular Targets and Mechanisms of 6,7-Dihydroxy-2,4-dimethoxyphenanthrene from Chinese Yam Modulating NF-κB/COX-2 Signaling Pathway: The Application of Molecular Docking and Gene Silencing

Chinese yam (Dioscorea opposita) tuber has a significant effect of invigorating the intestine and improving the symptoms of long-term diarrhea according to the records of the Chinese Pharmacopoeia. Phenanthrene polyphenols from Chinese yam, with higher inhibition of cyclooxygenase-2 (COX-2) than anti-inflammatory drugs, are an important material basis in alleviating ulcerative colitis via nuclear factor kappa-B (NF-κB)/COX-2 pathway, based on our previous research. The present study further explored the target and molecular mechanisms of phenanthrenes' modulation of the NF-κB/COX-2 signaling pathway by means of molecular docking and gene silencing. Firstly, interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) expression of 6-hydroxy-2,4,7-trimethoxyphenanthrene (PC2)/6,7-dihydroxy-2,4-dimethoxyphe-nanthrene (PC4) were compared on TNF-α induced human colon adenocarcinoma (Caco-2) cells. Secondly, molecular docking and dynamics simulation were implemented for PC2/PC4 and COX-2. Finally, COX-2 silencing was performed on TNF-α induced Caco-2 cells to confirm the target of PC4 on NF-κB/COX-2 pathway. Lower expression of IL-8 and TNF-α in PC4 treated Caco-2 cells indicated that PC4 had stronger anti-inflammatory activity than PC2. The binding of PC4 and COX-2 was stronger due to the hydrogen bond between hydroxyl group and Tyr385. No significant differences were found in phosphorylation nuclear factor kappa-B inhibitor alpha (pIkBα), phosphorylation NF-κB (pNF-κB) and phosphorylation extracellular signal-regulated kinase 1/2 (pERK1/2) expression between control and PC4 group after silencing, while these protein expressions significantly decreased in PC4 group without silencing, which confirmed that COX-2 was the important target for PC4 in alleviating ulcerative colitis. These findings indicate that PC4 was supposed to have inhibited NF-κB pathway mediated inflammation via suppression of positive feedback targeting COX-2.

Biogenic synthesis, molecular docking, biomedical and environmental applications of multifunctional CuO nanoparticles mediated Phragmites australis

The demand for metal nanoparticles is increasing with the widening application areas while causing environmental impact including pollution, toxic byproduct generation and depletion of natural resources. Incorporating natural materials in nanoparticle synthesis can contribute toward environmental sustainability. This paper is concerned with the biogenic synthesis of copper oxide nanoparticles (CuONPs) mediated by the plant species Phragmites australis. UV–vis, FT-IR, TEM and SEM studies were used to characterize the obtained CuONPs. The synthesized nanoparticles' antibacterial efficacy against Escherichia coli and Staphylococcus aureus was assessed. The CuONPs' reducing power, total phenolic component content, and flavonoid content were all calculated. Additionally, the dye removal abilities of copper oxide nanoparticles using Brilliant Blue R-250 were studied. The CuONP synthesis was assessed morphological by change of color and in the UV–vis analysis by the SPR band around 320 and 360 nm. FT-IR was used to monitor the functional groups present in the synthesized CuONPs. The obtained CuONPs were spherical and between 70 and 142 nm in size, according to the SEM data and TEM analyses were in accordance with SEM results. Using disk diffusion, the CuONPs demonstrated substantial antibacterial efficacy against S. aureus and E. coli, with inhibition zones of 18.5 ± 0.8 and 12.7 ± 0.6 mm, respectively. The MBC and MIC values were 62.5 μg/mL against S. aureus and 125 μg/mL against E. coli. The antioxidant abilities of P. australis and CuONPs were also confirmed. The CuONP solution's total phenolic substance content was 9.44 μg of pyrocathecol equivalent per milligram of nanoparticle, and its total flavonoid content was 16.24 μg of catechin equivalent per milligram of nanoparticle. Additionally, the synthesized CuONPs were found to be well effective on industrial dye removal by demonstrating high decolorization of 98 %. Also, the antibacterial activity of CuONPs was investigated through the interactions with S. aureus FtsZ, dihydropteroate synthase and thymidylate kinase. In silico molecular docking analysis was applied in the confirmation of the binding sites and interactions of active sites. CuONP showed −9.067, −8,048, and −7.349 kcal/mol of binding energies in molecular docking analysis of FtsZ, dihydropteroate synthase and thymidylate kinase proteins respectively. The results of this study suggested the antimicrobial, antioxidant and decolorative effect of synthesized CuONPs that can be apply in multiple areas of R&D and industry.

Structure-based virtual screening of novel natural products as chalcone derivatives against SARS-CoV-2 Mpro

Coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2, has spread quickly around the world, causing a global pandemic. It has infected more than 500 million people as of April 28, 2022. Much research has been reported to stop the virus from spreading, but there are currently no approved medicines to treat COVID-19. In this work, a dataset of 142 natural products collected from various medicinal plants was used to perform structure-based virtual screening (SBVS) through the combined application of molecular docking and molecular dynamics (MD) simulation methods. First, the dataset of compounds was optimized using the density functional theory (DFT) approach. The optimized compounds were then submitted to the first screening, which was done by the pKCM web server to look for drug-likeness and the PyRx to look for binding affinity. Among the 142 natural substances, 10 compounds were selected for docking validation. Compounds that interact with CYS145 and LEU141, the essential catalytic residues, as well as compounds with binding affinities less than −8.0 kcal/mol, are considered promising anti-SARS-CoV-2 drug candidates. The top-ranked compounds were then evaluated by MD simulations and MM-GBSA method. These results could help researchers come up with new natural compounds that could be used to treat SARS-CoV-2. Communicated by Ramaswamy H. Sarma

In-vitro Bioevaluation, Pharmacokinetics and Molecular Docking Study of unexplored Bisabolol-rich Curcuma inodora essential oil from Konkan region: A biodiversity hotspot

Curcuma inodora Blatt., belonging to the Zingiberaceae family is an endemic species from peninsular India. The extraction and some of the biological applications of leaves essential oil of this species had been reported from South India. Although the Konkan region is a biodiversity hotspot, no report on the medicinal applications of essential oils in this species is available to date. Herein, the ?–Bisabolol-rich rhizome essential oil from wild C. inodora was isolated by the hydrodistillation method and characterized by Gas Chromatography-Flame ionization detector (GC/ GC-FID) and Gas Chromatography High-resolution mass spectrometry (GC/HRMS) techniques for pharmacokinetics and molecular docking applications. The Hydrodistillation extract (HDREO) constituted 11 components with a major constituent, ?- Bisabolol (62.13%). In-vitro anti-bacterial, anti-fungal, anti-oxidant, and anti-inflammatory potential of rhizome oils were carried out. The pharmacokinetics of the major component, ?-Bisabolol, like high GI absorption, zero Lipinski violation with good bioavailability score, etc. support its candidacy as a drug. Further, docking was performed with the principal component ?- Bisabolol. The least binding energy conformation of ?–Bisabolol with anti-bacterial (3WGN.pdb), anti-fungal (1IYL.pdb), anti-oxidant (3MNG.pdb) and anti-inflammatory (1CX2.pdb) proteins were reported to be -7.01 kcal/mol, -8.15 kcal/mol, -7.82 kcal/mol, and –7.71 kcal/mol respectively. This shows, the significant binding affinity of ?–Bisabolol with proteins. So, the rhizome oil of this unexplored species can be utilized in developing novel phytopharmaceuticals and medicines after further study. To the best, this is a foremost report on the rhizome essential oil isolation by hydrodistillation method, its characterization, and its bio-evaluation with pharmacokinetics and docking applications of this species.

Binding Pattern Analysis of Different Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase

To the best of our knowledge, the current study could be considered the first comprehensive one based on the application of molecular docking on the non-nucleoside thumb and palm inhibitors to nonstructural NS5B protein for the detailed evaluation of their binding patterns in the corresponding binding regions in the protein. Non-nucleoside thumb and palm inhibitors were docked into the thumb and palm sites of the nonstructural NS5B protein which is the RNA-dependent RNA polymerase, respectively. Two docking programs, AutoDock 4.2 and AutoDock Vina were employed for the docking of thumb inhibitors (filibuvir and lomibuvir) and palm inhibitors (dasabuvir and nesbuvir) into the respective binding region. The preliminary analysis of the docking performance demonstrated that AutoDock Vina was suitable for the docking of large flexible molecules as deduced from the alignment of docking conformations in all cases. Based on the docking calculation, the interaction pattern analysis was carried out for all the inhibitors which were found to reside in the respective binding region. Before the interaction pattern analysis, the best docking pose was selected based on the high binding affinity value. The interaction pattern analysis of the inhibitors revealed that hydrogen bonding and hydrophobic contacts with amino acid residues of the respective binding region were the leading force in the stabilization of these inhibitors besides other interactions. The interaction pattern analysis based on the docking calculation was also realized to be the meaningful approach to figuring out the relative stability of the protein-ligand complex formed after the inhibitor binding which eventually led to assessing the inhibitory potential of these inhibitors and could also be helpful for the future inhibitor design.

Computational strategies for PROTAC drug discovery

Proteolysis-targeting chimeras (PROTACs), a novel targeted protein degradation technology for potential clinical drug discovery, is composed of a protein-targeting ligand covalently linked to an E3 ligase ligand. Through recruiting E3 ligase to target proteins, PROTACs elicit ubiquitination and subsequent degradation of targets via the ubiquitin-proteasome system. In the past few decades, molecular docking and virtual screening have emerged as an efficient strategy in drug discovery for identifying compounds from a large database of chemical structures. For PROTACs, molecular docking accurately simulates the protein-PROTAC-E3 ternary complex, thus greatly accelerating structure-activity-relationship analysis, and improving ligand affinity and selectivity. In this review, we summarize recent efforts in the application of molecular docking and virtual screening for PROTAC drug discovery. To date, approximately nine target proteins and twelve PROTACs have been successfully developed through molecular docking and virtual screening. Finally, the potential challenges of molecular docking and virtual screening-based PROTACs are discussed.

Hierarchical analysis of the target-based scoring function modification for the example of selected class A GPCRs.

Computational methods, especially molecular docking-based calculations, have become indispensable in the modern drug discovery workflow. The constantly increasing chemical space requires fast, robust but most of all highly predictive methods to search for new bioactive agents. Thus, the scoring function (SF) is a useful and broadly applied energy-based element of docking software, allowing quick and effective evaluation of a ligand's propensity to bind to selected protein targets. Despite many spectacular successes of molecular docking applications in virtual screening (VS), the obtained results are often far from ideal, leading to incorrect selection of hit molecules and poor pose prediction. In our study we focused on docking calculation for the selected class A G-protein coupled receptors (GPCRs), with experimentally determined 3D structures and a sufficient set of known ligands with affinity values reported in the ChEMBL database. Our goal is to investigate how much the energy-based scoring function for this particular target class changes when changing from the default to the re-estimated weighting scheme on the specified energy terms in the SF definition. Additionally, we want to verify if indeed more accurate results are obtained when considering different levels of the biological hierarchy, namely: the whole class A GPCRs, sub-subfamilies, or just the individual proteins while applying default or specifically designed weighting coefficients. The performed calculation and evaluation factor values suggest a significant improvement of docking results for the designed SF definition. This individual approach improves the accuracy of binding affinity prediction and active compound recognition. The designed scoring function for classes, sub-subfamilies, or proteins leads to a significant improvement of molecular docking performance, especially at the level of individual proteins. Our results show that to increase the efficiency and predictive power of molecular docking calculations applied in classical VS, the strategy based on the individual approach for scoring function definition for selected proteins should be considered.

Molecular Docking Studies and Application of 6-(1-Arylmethanamino)-2-Phenyl-4H-Chromen-4-Ones as Potent Antibacterial Agents

The present article depicts the synthesis of the series of 6-(1-arylmethanamino)-2-phenyl-4H-chromen-4-ones and their antibacterial activity against the S. aureus. 6-(1-arylmethanamino)-2-phenyl-4H-chromen-4-ones (1a–1n) were obtained via reductive amination reaction of 6-aminoflavone with various commercially available aldehydes. Synthesized compounds and 6-aminoflavone (1) were assessed for their antimicrobial activities against the S. aureus. 6-aminoflavone (1) was found to have an MIC of 2 µg/mL. The compounds with side chains 4-fluorobenzyl (1a), 4-chlorobenzyl (1b), 4-nitrobenzyl (1e), 4-methoxybenzyl (1g) and (quinolin-2-yl)methyl (1n) were found to have an MIC of 2 µg/mL. We have demonstrated that 6-(1-arylmethanamino)-2-phenyl-4H-chromen-4-ones are easily accessible via reductive amination reaction. These compounds are found to have antibacterial effect against S. aureus.

Redesigning and Optimizing UCSF DOCK3.7 on Sunway TaihuLight

Molecular docking is the process of posing, scoring, and ranking small molecules at the binding sites of proteins to prioritize compounds for experimental testing. It is a widely-used computational method in the drug discovery process. However, it is a highly time-consuming procedure since a receptor may need to find favorable ligand orientations in billions of ligands. UCSF DOCK3.7 is one of the most widely used molecular docking applications. In this paper, we port and optimize UCSF DOCK3.7 on the Sunway TaihuLight supercomputer. To avoid the impact of load imbalance, we employ a producer-consumer strategy that can overlap I/O and computation in order to achieve high performance. Furthermore, we present a new binary file format to replace the mol2db2 file format for ligand storage and adopt xzip rather than gzip to compress ligand files. We show that our file format can reduce I/O time significantly while xzip saves significant storage. For the routines which determine the orientation of a ligand relative to the receptor, we present an improved algorithm to discard geometrically similar orientations. Furthermore, we fuse loops and compress memory usage to store data in fast Local Device Memory (LDM) in order to score ligand orientations with high efficiency. In addition, we propose a number of architecture-specific optimizations. Asynchronous data transfer and vectorization of computation are implemented to take full advantage of the SW26010 processor. Our experiments show that a speedup of 167 can be achieved by using the proposed strategies. Compared to a core of an Intel(R) Core(TM) i9-10900K CPU, our approach achieves speedups of 15 on a SW26010 core group. Furthermore, our implementation achieves strong scalability to hundreds of thousands of heterogeneous cores on the next-generation Sunway supercomputer.

WITHDRAWN: Molecular docking used as an advanced tool to determine novel compounds on emerging infectious diseases: A systematic review

Emerging infectious diseases (EID) as well as reappearing irresistible infections are expanding worldwide. Utmost of similar cases, it was seen that the EIDs have long been perceived as a predominant conclusion of host-pathogen adaption. Here, one should get to analyze their host-pathogen interlink and their by needs to look ways, as an example, by exploitation process methodology particularly molecular docking and molecular dynamics simulation, have been utilized in recent time as the most outstanding tools. Hence, we have overviewed some of important factors that influences on EIDs especially HIV/AIDs, H1N1 and coronavirus. Moreover, here we specified the importance of molecular docking applications especially molecular dynamics simulations approach to determine novel compounds on the emerging infectious diseases. Additionally, in vivo and in vitro studies approach to determine novel compounds on the emerging infectious diseases that has implemented to evaluate the limiting affinities between small particles as well as macromolecule that can further, used as a target of HIV/AIDs, H1N1, and coronavirus were also discussed. These novel drug molecules approved in vivo and in vitro studies with reaffirm results and hence, it is clear that the computational methods (mainly molecular docking and molecular dynamics) are found to be more effective technique for drug discovery and medical practitioners.

Investigation into the potential mechanism and molecular targets of Fufang Xueshuantong capsule for the treatment of ischemic stroke based on network pharmacology and molecular docking.

Fufang Xueshuantong (FFXST) capsule is a traditional Chinese medicine (TCM) preparation used to activate blood circulation, resolve stasis, benefit qi, and nourish yin in clinical practice. However, its potential mechanism and molecular targets after ischemic stroke (IS) have not been investigated. The aim of this research was to investigate the molecular mechanisms of FFXST in the treatment of IS based on network pharmacology and molecular docking. We used the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) to collect candidate compounds of four herbs in FFXST; disease-related differential genes were screened using the Gene Expression Omnibus (GEO) database, and a compound–disease network was created using Cytoscape 3.8.2 software. The topological analysis of the protein–protein interaction (PPI) network was then created to determine the candidate targets of FFXST against IS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the clusterProfiler package in R. The gene–pathway network of FFXST against IS was created to obtain the key target genes. Molecular docking was used to validate the core targets using AutoDock Vina 1.1.2. A total of 455 candidate compounds of FFXST and 18,544 disease-related differential genes were screened. Among them, FFXST targets for IS treatment had 67 active compounds and 10 targets in the PPI network related to STAT1, STAT3, and HIF1A. The biological processes of GO analysis included the regulation of reactive oxygen species metabolic process, cellular response to chemical stress, regulation of angiogenesis, regulation of vasculature development, positive regulation of cytokine production, and response to oxidative stress. The KEGG enrichment analysis showed that Kaposi sarcoma-associated herpesvirus infection, microRNAs in the cancer signaling pathway, Th17 cell differentiation, and HIF-1 signaling pathway were significantly enriched. The network pharmacology outcomes were further verified by molecular docking. We demonstrated that FFXST protection against IS may relate to the regulation of oxidative stress, immune inflammatory response, and angiogenesis through the relevant signaling pathways. Our study systematically illustrated the application of network pharmacology and molecular docking in evaluating characteristics of multi-component, multi-target, and multi-pathway of FFXST for IS.

Single-step green synthesis of gold conjugated polyphenol nanoparticle using extracts of Saudi’s myrrh: Their characterization, molecular docking and essential biological applications

The progress in the innovative nanocrystal synthesis process by using environmentally benign and low-priced nontoxic chemicals, solvents, and renewable sources remains a challenging task for researchers worldwide. The majority of the existing synthesis techniques engage in the potentially dangerous, for either human health or the environment. Current investigation has been centered on green synthesis processes to create novel nanomaterials, which are eco-friendly as well as safer for sustainable marketable feasibility. The current work provides the green synthesis method for gold nanoparticle (GNPs) synthesis using Commiphora myrrh (C.myrrh) extract. This simple method includes 6 ml of HAuCl4·3H2O treated with 4 ml C.myrrh extract having pH 4.5 after 80 min at 25 °C temperature. In this novel method, green synthesized GNPs characterized by UV–Vis, X_ray diffraction spectroscopy (XRD), zeta potential, fourier transform infrared (FT_IR), high_resolution transmission electron microscopy (HR_TEM), energy dispersive X_ray spectroscopy (EDXA), and dynamic light scattering (DLS). During the development successful antioxidant assay, the DPPH assay was applied. The cell toxicity of green synthesized GNPs was evaluated following an MTT assay against HCT-116 (colon cancer) and MCF-7 (breast cancer).Besides molecular docking in the δ-elemene for inhibitor to VEGFR‐2 domain revealed more negative docking score (−3.976) which is an excellent binding affinity to the C.myrrh@GNP. The synthesized GNPs showed antidiabetic, antibiotic, and antibacterial properties and anti_inflammatory inhibition against inhibiting COX-1, and COX-2 enzymes. In addition, molecular docking by Lindestrene (−3.806) and Furanoeudesma-1,3-dien (−3.912) against COX1 and COX2 respectively showed strong binding affinity. The molecular docking study evidenced the anti-inflammatory and cell toxicity study.

Discovery of novel Glutaminase allosteric inhibitors through drug repurposing and comparative MMGB/PBSA and molecular dynamics simulation

GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and colorectal. To date, several medicinal chemistry studies are being conducted to develop new and effective inhibitors against GLS1 enzymes. Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone clinical trials for the first time for the therapy of solid tumors and hematological malignancies. A comprehensive computational investigation is performed to get insights into the inhibition mechanism of the Telaglenastat. Some novel inhibitors are also proposed against GLS1 enzymes using the drug repurposing approach using 2D-fingerprinting virtual screening method against 2.4 million compounds, application of pharmacokinetics, Molecular Docking, and Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 Å was defined to solvate both enzymes to improve MD simulation reliability. The dynamics results were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD analysis. Results of these computational analysis revealed a stable binding affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC50 ∼ 0.9 nM) and a novel para position oriented methoxy group containing Chembridge compound (Chem-64284604) that provides an effective inhibitory action against GAC and KGA.

Identifying SARS-CoV-2 main protease inhibitors by applying the computer screening of a large database of molecules

ABSTRACT The outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019 affected global health. Its infection agent was called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Wearing a mask, maintaining social distance, and vaccination are effective ways to prevent infection of SARS-CoV-2, but none of them help infected people. Targeting the enzymes of SARS-CoV-2 is an effective way to stop the replication of the virus in infected people and treat COVID-19 patients. SARS-CoV-2 main protease is a therapeutic target which the inhibition of its enzymatic activity prevents from the replication of SARS-CoV-2. A large database of molecules has been searched to identify new inhibitors for SARS-CoV-2 main protease enzyme. At the first step, ligand screening based on similarity search was used to select similar compounds to known SARS-CoV-2 main protease inhibitors. Then molecules with better predicted pharmacokinetic properties were selected. Structure-based virtual screening based on the application of molecular docking and molecular dynamics simulation methods was used to select more effective inhibitors among selected molecules in previous step. Finally two compounds were considered as SARS-CoV-2 main protease inhibitors.

Exploring the mechanisms of action of Cordyceps sinensis for the treatment of depression using network pharmacology and molecular docking.

BackgroundDepression is the most common type of psychological disorder, with continuous, prolonged, and persistent bad moods as the main clinical feature. Cordyceps sinensis is a complex consisting of the ascospores and bodies of insect larvae from the Hepialidae family that have been parasitized by Cordyceps sinensis militaris. Previous studies have reported that this herb has antidepressant activity. The present study used network pharmacology and molecular docking techniques to investigate the potential antidepressant mechanisms of Cordyceps sinensis.MethodsThe active ingredients of Cordyceps sinensis were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the potential targets were predicted using the PharmMapper platform. The GeneCards database was then used to obtain sub-targets for depression. Common targets were screened and enrichment analyses were performed using the Metascape platform. Finally, the relationship between the active ingredients and the core targets were verified by molecular docking.ResultsThrough network pharmacological analysis, 7 active ingredients in Cordyceps sinensis and 41 common targets of drugs and diseases were identified. The active ingredients of Cordyceps sinensis may exert antidepressant effects by acting on important targets such as catalase (CAT), CREB binding protein (CREBBP), epidermal growth factor (EGF), and E1A binding protein P300 (EP300), and by modulating the signaling pathways in which these targets are involved. Subsequently, the core targets were docked to the active ingredients and good binding was observed.ConclusionsThe active ingredients of Cordyceps sinensis may exert antidepressant effects by regulating the CREB binding protein and anti-oxidative stress effects. The foxo signaling pathway (hsa04068), hypoxia-inducible factor 1 (HIF-1) signaling pathway (hsa04066), and Huntington’s disease (hsa05016) may be involved in the underlying mechanisms of Cordyceps sinensis. The joint application of network pharmacology and molecular docking provides a new approach to study the mechanisms of action of traditional Chinese medicine. Cordyceps sinensis may play an important role in the future treatment of patients with depression.

Luteolin Potentially Treating Prostate Cancer and COVID-19 Analyzed by the Bioinformatics Approach: Clinical Findings and Drug Targets.

Coronavirus disease 2019 (COVID-19) is a serious epidemic, characterized by potential mutation and can bring about poor vaccine efficiency. It is evidenced that patients with malignancies, including prostate cancer (PC), may be highly vulnerable to the SARS-CoV-2 infection. Currently, there are no existing drugs that can cure PC and COVID-19. Luteolin can potentially be employed for COVID-19 treatment and serve as a potent anticancer agent. Our present study was conducted to discover the possible drug target and curative mechanism of luteolin to serve as treatment for PC and COVID-19. The differential gene expression of PC cases was determined via RNA sequencing. The application of network pharmacology and molecular docking aimed to exhibit the drug targets and pharmacological mechanisms of luteolin. In this study, we found the top 20 up- and downregulated gene expressions in PC patients. Enrichment data demonstrated anti-inflammatory effects, where improvement of metabolism and enhancement of immunity were the main functions and mechanism of luteolin in treating PC and COVID-19, characterized by associated signaling pathways. Additional core drug targets, including MPO and FOS genes, were computationally identified accordingly. In conclusion, luteolin may be a promising treatment for PC and COVID-19 based on bioinformatics findings, prior to future clinical validation and application.