Discovery Studio Client Research Articles

Employing Hexahydroquinolines as PfCDPK4 Inhibitors to Combat Malaria Transmission: An Advanced Computational Approach.

Existing antimalarial drugs primarily target blood-stage parasites, but there is a need for transmission-blocking drugs to combat malaria effectively. Plasmodium falciparum Calcium-dependent Protein Kinase 4 (CDPK4) is a promising target for such drugs. This study employed advanced in silico analyses of hexahydroquinolines (HHQ) derivatives to identify PfCDPK4 inhibitors capable of disrupting malaria transmission. Structure-based virtual screening (SBVS) was employed to discover HHQ derivatives with the highest binding affinities against the 3D structure of PfCDPK4 (PDB 1D: 4QOX). Interaction analysis of protein-ligand complexes utilized Discovery Studio Client, while druglikeness and ADMET properties were assessed using SwissADME and pkCSM web servers, respectively. Quantum mechanical calculations of the top hits were conducted using density functional theory (DFT), and GROMACS was employed to perform the molecular dynamics (MD) simulations. Binding free energy was predicted using the MMPBSA.py tool from the AMBER package. SBVS identified ten best hits possessing docking scores within the range of -11.2 kcal/mol and -10.6 kcal/mol, surpassing the known inhibitor, BKI-1294 (-9.9 kcal/mol). Among these, 4-[4-(Furan-2-carbonyl)piperazin-1-yl]-1-(naphthalen-2-ylmethyl)-2-oxo-4a,5,6,7,8,8a-hexahydroquinoline-3-carbonitrile (PubChem ID: 145784778) exhibited the highest binding affinity (-11.2 kcal/mol) against PfCDPK4. Comparative analysis of this compound with BKI-1294 using advanced computational approaches demonstrated competitive potential. These findings suggest the potential of 4-[4-(Furan-2-carbonyl)piperazin-1-yl]-1-(naphthalen-2-ylmethyl)-2-oxo-4a,5,6,7,8,8a-hexahydroquinoline-3-carbonitrile as a promising PfCDPK4 inhibitor for disrupting malaria transmission. However, further experimental studies are warranted to validate its efficacy and safety profile.

In-silico studies and docking of n-substituted isoindoline-1, 3-dioine analogues as anti-proliferative agents

Recently,isoindoline-1,3-dione compounds based folpet, phosmet, captonand thalidomide were developed because they have a comparable degree of anti-proliferative efficacy owing to their diverse mechanisms such as HDAC inhibitors, tryptase inhibitors, inhibits the mode of tnf-α, and angiogenesis inhibitors. It was investigated how the phthalimide pharmacophore interacted with molecules such tnf-α, HDAC, VEGF, EGF, and Tyrosine Kinase Angiogenesis. In order to assess the inhibitory activity against enzyme assay, a series of phthalimidepharmacophores with various substituent’s (Schiff's base) at the N-phenyl ring were submitted to protein-ligand docking investigations using the lib-dock method in the current work. All of the compounds' chemical structures were designed using Cambridge software, ChemBioOffice Ultra 12.0, and their molecular characteristics were determined using the online molecular modelling tool Molinspiration. Utilizing the Discovery Studio Client version 4.1, ADMETlab 2.0, and Lazar 1.4.2 softwares, ADME, Toxicity, and Molecular Docking investigations using the lib-dock method were carried out to evaluate the binding mode and interactions of synthetic hits at the binding site of receptors. Docking studies demonstrated that these sorts of ligands interacted mostly with TNF-α, HDAC, VEGF, EGF, Tyrosine kinase, and angiogenesis reports, among others, by forming hydrogen bonds and interacting hydrophobically with the domain. Our docking results indicate that compounds A1, A10, A11, A22, A26, and A28 demonstrated the greatest binding affinity with the corresponding proteins based on the predicted binding energy. These computer simulations have shown that phthalimide compounds with N-phenyl rings replaced can effectively suppress enzymatic assay.

Determination of the inhibition effect of hesperetin and its derivatives on Candida glabrata by molecular docking method

In the study, it was aimed to develop new candidate inhibitor molecules by targeting the AWP1 protein structure of Candida glabrata organism. Hesperetin molecule was taken as a reference and different substituted groups were attached to the determined ends of the molecule to increase the inhibition potential on the protein structure. A total of 100 molecules were designed and after conformer distribution using the Molecular Mechanics/MMFF method for each designed molecule, the area, volume, weight, energy, EHOMO, ELUMO, polarizability, dipole moment, log P values of these molecules were calculated using the Semi Empirical/PM6 method. Molecular docking studies of the optimized molecules were carried out through the Autodock Vina program. After the docking studies, the interactions of the designed molecules with the active site amino acids of the protein structure were analyzed by BIOVIA Discovery Studio Client software in case of possible mutation. As a result of the analysis, five molecules with higher binding energies than other designed molecules and currently used antifungal drugs were recommended.

In-Silico Analysis of Polyphenol Compounds in Pomegranate Fruit (Punica granatum L.) Peel Potential as type 2 Antidiabetes Mellitus

Diabetes mellitus is a disease characterized by increased blood sugar levels due to insulin resistance caused by the uncontrolled expression of the protein tyrosine phosphatase 1B (PTP1B). Several compounds that inhibit PTP1B have been studied, including polyphenol. Many studies have been conducted on diabetes medicines based on natural ingredients, including the pomegranate fruits (Punica granatum L). This study aims to test the inhibitory activity of polyphenolic compounds in pomegranate peel (gallic acid, caffeic acid, ellagic acid, chlorogenic acid, apigenin, quercetin, pelargonidin, and cyanidin) against PTP1B through molecular docking. The 3D structures of polyphenolic compounds were obtained from the PubChem database, while PTP1B was from the Protein Data Base. Molecular docking simulations were carried out using AutoDock Vina and several supporting softwares, such as Biovia Discovery Studio Client 4.1, AutoDockTools 1.5.6, PyMOL, and LigPlot. Molecular docking results showed that polyphenolic compounds from pomegranate peel have good inhibitory potential against PTP1B. It is proven by the binding affinity value for PTP1B, which is low and negative, namely in the range -6.4 to -8.4 kcal/mol, and the inhibition constant in the range 0.69 to 20,12 µM. The presence of phenol and carboxylic acid groups in polyphenol compounds can strengthen ligand-protein complexes through hydrogen bonds, especially with the amino acid residues Gln221 and Cys215. The potential of polyphenolic compounds as antidiabetics is also supported by van der Waals interactions and π-π stacking interactions with PTP1B. Based on the molecular docking test that has been carried out, it can be concluded that the polyphenolic compounds in pomegranate peel have the potential to act as type 2 anti-diabetes mellitus.

A real-world study and network pharmacology analysis of EGFR-TKIs combined with ZLJT to delay drug resistance in advanced lung adenocarcinoma

ObjectiveThis study aimed to explore the efficacy and safety of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with ZiLongJin Tablet (ZLJT) in delaying acquired resistance in advanced EGFR-mutant lung adenocarcinoma (LUAD) patients. Furthermore, we employed network pharmacology and molecular docking techniques to investigate the underlying mechanisms.MethodsA retrospective comparative study was conducted on stage IIIc/IV LUAD patients treated with EGFR-TKIs alone or in combination with ZLJT at the Second Affiliated Hospital of the Air Force Medical University between January 1, 2017, and May 1, 2023. The study evaluated the onset of TKI resistance, adverse reaction rates, safety indicators (such as aspartate aminotransferase, alanine aminotransferase, and creatinine), and inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) to investigate the impact of EGFR-TKI combined with ZLJT on acquired resistance and prognostic indicators. Additionally, we utilized the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine, PubChem, UniProt, and Swiss Target Prediction databases to identify the active ingredients and targets of ZLJT. We obtained differentially expressed genes related to EGFR-TKI sensitivity and resistance from the Gene Expression Omnibus database using the GSE34228 dataset, which included sensitive (n = 26) and resistant (n = 26) PC9 cell lines. The "limma" package in R software was employed to detect DEGs. Based on this, we constructed a protein‒protein interaction network, performed gene ontology and KEGG enrichment analyses, and conducted pathway network analysis to elucidate the correlation between the active ingredients in ZLJT and signaling pathways. Finally, molecular docking was performed using AutoDockVina, PYMOL 2.2.0, and Discovery Studio Client v19.1.0 software to simulate spatial and energy matching during the recognition process between predicted targets and their corresponding compounds.Results(1) A total of 89 patients were included, with 40 patients in the EGFR-TKI combined with ZLJT group (combination group) and 49 patients in the EGFR-TKI alone group (monotherapy group). The baseline characteristics of the two groups were comparable. There was a significant difference in the onset of resistance between the combination group and the monotherapy group (P < 0.01). Compared to the monotherapy group, the combination group showed a prolongation of 3.27 months in delayed acquired resistance. There was also a statistically significant difference in the onset of resistance to first-generation TKIs between the two groups (P < 0.05). (2) In terms of safety analysis, the incidence of adverse reactions related to EGFR-TKIs was 12.5% in the combination group and 14.3% in the monotherapy group, but this difference was not statistically significant (P > 0.05). There were no statistically significant differences in serum AST, ALT, CREA, TBIL, ALB and BUN levels between the two groups after medication (P > 0.05). (3) Regarding inflammatory markers, there were no statistically significant differences in the changes in neutrophil-to-lymphocyte Ratio(NLR) and Platelet-to-lymphocyte Ratio(PLR) values before and after treatment between the two groups (P > 0.05). (4) Network pharmacology analysis identified 112 active ingredients and 290 target genes for ZLJT. From the GEO database, 2035 differentially expressed genes related to resistant LUAD were selected, and 39 target genes were obtained by taking the intersection. A "ZLJT-compound-target-disease" network was successfully constructed using Cytoscape 3.7.0. GO enrichment analysis revealed that ZLJT mainly affected biological processes such as adenylate cyclase-modulating G protein-coupled receptor. In terms of cellular components, ZLJT was associated with the cell projection membrane. The molecular function primarily focused on protein heterodimerization activity. KEGG enrichment analysis indicated that ZLJT exerted its antitumor and anti-drug resistance effects through pathways such as the PI3K-Akt pathway. Molecular docking showed that luteolin had good binding activity with FOS (-9.8 kJ/mol), as did tanshinone IIA with FOS (-9.8 kJ/mol) and quercetin with FOS (-8.7 kJ/mol).ConclusionZLJT has potential antitumor progression effects. For patients with EGFR gene-mutated non-small cell LUAD, combining ZLJT with EGFR-TKI treatment can delay the occurrence of acquired resistance. The underlying mechanisms may involve altering signal transduction pathways, blocking the tumor cell cycle, inhibiting tumor activity, enhancing cellular vitality, and improving the bioavailability of combination therapy. The combination of EGFR-TKI and ZLJT represents an effective approach for the treatment of tumors using both Chinese and Western medicine.

Novel therapeutic targets for the treatment of oral cancer with compounds identified in Wrightia tinctoria: An in silico docking study with oncogenic pathways

Introduction: Oral cancer is the sixth most common cancer worldwide. According to scientific data on oral cancer, the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) are two important causative pathways responsible for cellular proliferation in oral cancer. In the current research, two chemical compounds, 3-O-methyl-d-glucose and squalene, identified in Wrightia tinctoria extract, were used to study their action on the EGFR and MAPK pathways using molecular docking to prevent oral cancer progression. Materials and Methods: A molecular docking analysis was carried out based on the chemical makeup and similarities of chemicals derived from the plant with the target oncogenic proteins EGFR and MAPK. Following protein synthesis by Biovia Discovery Studio Visualizer, ligands were imported for virtual screening using PyRx, a program for computational drug discovery for the virtual screening of libraries of compounds against therapeutic targets. Results: The molecular docking investigation between 3-O-methyl-d-glucose, squalene, and the oncogenic pathways EGFR and MAPK was conducted using the Biovia Discovery Studio Client 2021 and AutoDock Vina software. In contrast to squalene, which exhibited an inhibitory constant of 44.99 µM and a ligand efficacy of 0.20, 3-O-methyl-d-glucose had an effective inhibitory constant (10.5 mM) on EGFR and MAPK. Both substances hindered the LSY721 binding site, which in turn suppressed the activity of oncogenic progression. Conclusion: 3-O-methyl-d-glucose and squalene found in W. tinctoria can inhibit the progressive activity of cancer-causing proteins (EGFR, MAPK) in oral cancer. 3-O-methyl-d-glucose was found to inhibit the oncogenic proteins more efficiently than squalene.

Exploring the phytoconstituents targeting TNF-α as potential lead compounds to treat inflammatory diseases: an in-silico approach

To explore the anti-inflammatory phytoconstituents from various plant sources as tumour necrosis factor- α (TNF- α )-inhibitor, a mediator involved in the inflammatory disorder, by in silico molecular docking. Based on previous findings, we performed the in silico assessment of anti-inflammatory phytoconstituents from different medicinal plants to understand their binding patterns against TNF- α (PDB ID: 6OP0) using AutoDock Vina. Molecular docking was performed by setting a grid box (25 × 25 × 25) Å centered at [– 12.817 × (– 1.618) × 19.009] Å with 0.375 Å of grid spacing. Furthermore, Discovery Studio Client 2020 program was utilized to assess two- and three-dimensional (2D and 3D) hydrogen-bond interactions concerning an amino acid of target and ligand. Physicochemical properties were reported using the Lipinski’s rule and SwissADME database to support the in silico findings. Results From the selected medicinal plants, more than 200 phytocompounds were screened against TNF- α protein with binding scores in the range of – 12.3 to – 2.5 kcal/mol. Amongst them, emodin, aloe-emodin, pongamol, purpuritenin, semiglabrin, ellagic acid, imperatorin, α -tocopherol, and octanorcucurbitacin A showed good binding affinity as – 10.6, – 10.0, – 10.5, – 10.1, – 11.2, – 10.3, – 10.1, – 10.1, and – 10.0 kcal/mol, respectively. Also, the absorption, distribution, metabolism, excretion, and toxicology (ADMET) profiles were well within acceptable limits. Based on our preliminary findings, we conclude that the selected phytoconstituents have the potential to be good anti-inflammatory candidates by inhibiting the TNF- α target. These compounds can be further optimized and validated as new therapeutic components to develop more effective and safe anti-inflammatory drugs. (i) Inflammation is a global clinical issue that involves several bio-chemical mediators. (ii) Phytoactive compounds are known to exhibit remarkable anti-inflammatory activities in traditional as well as some modern medicines. (iii) This study covers an in silico tool based findings that throw light on plant based bioactive compounds with potential for anti-inflammatory activity by inhibiting TNF- α. (iv) Precisely, 203 phyto-compounds were screened against target protein TNF- α trimer to find “best fit” based on docking score, binding energies, ADME studies, toxicity prediction, drug likeness, and molecular interactions.

Anti-Diabetic Potential of Gymnema Sylvestre: In Vitro and in Silico Analysis

Gymnema sylvestre (GS) is a powerful antidiabetic plant that has been utilized in ayurvedic, folk and homeopathic medicine for centuries. In this research, we evaluated the antidiabetic potential of methanolic leaf extract of Gymnema sylvestre. Fractionation was carried out using column chromatography and a total of twenty-eight (28) sub-fractions were obtained which were further screened and pooled into three (3) fractions (A, B and C) by thin layer chromatography based on their retention factor (Rf) values. The fractions were subjected to in vitro α-amylase and α-glucosidase inhibition activity. Some of the compounds identified from LC-MS were subjected to in silico analysis between all the ligands and the receptors with the aid of a docking software. Ligands were imported for visual screening into PyRx software while Biovia Discovery Studio Visualizer was used for protein preparation. Analysis of the properties of drug likeliness of the ligands was done via SwissADME online server according to Lipinski’s Rule of Five. Final docking analysis was done through AutoDockVina and Biovia Discovery Studio client 2020. Fraction C showed the best IC50 of 0.84µg/ml α-glucosidase inhibitory activity when compared with fraction A and B, 2.00µg/ml and 1.58µg/ml (α-glucosidase), fraction A produced the best α-amylase activity among the fractions with IC50 of 16.78µg/ml, fraction B with 23.17µg/ml and fraction C with 28.22µg/ml. Molecular docking analysis of the ligands Orcinol (-5.5 kcal/mol) showed strong binding interaction with α-amylase, followed by 3-hydroxy-3'-methoxyflavone and Curcumin (-7.1 kcal/mol and -7.6 kcal/mol respectively) compared to acarbose (-8.0 kcal/mol) and Glyinflanin A (-8.4 kcal/mol) interactions. The binding affinity of Orcinol, 3-hydroxy-3'-methoxyflavone, Curcumin and Glyinflanin A (-5.7 kcal/mol, -8.0 kcal/mol, -7.6 kcal/mol and -9.1 kcal/mol respectively) were lower compared to acarbose (-9.7 kcal/mol) interaction with α-glucosidase. Thus, compounds identified from Gymnema sylvestre were found to have antidiabetic potentials with Orcinol displaying the most effective binding affinity in potential for drug development.

Structure Based Docking of Secondary Metabolites against Alpha-amylase and Alpha-glucosidase Activities in Treating Diabetes

Diabetes mellitus (DM) is a long term disorder of metabolism characterized by high level of blood sugar (hyperglycemia) due to insufficient secretion of insulin, insulin resistance, or both, as well as poor lipid, protein and carbohydrate metabolism. These complications occur as a result of derangement in glucose storage for the regulatory system and metabolic fuel mobilization, including carbohydrate, protein and lipid anabolism and catabolism emanating from impaired action of insulin, secretion of insulin, or both. The in silico study was conducted with the help of molecular docking to treat diabetes to inhibit the activities of α-amylase and α-glucosidase by drug molecule. All the studies were based on docking with molecules. The docking was done using a docking software between all the ligands and the target protein receptors. Natural compounds, such as Conduritol A, Catechin and Quercetin were picked, and protein targets as α-amylase and α-glucosidase. Ligands were imported for visual screening into PyRx software while Biovia Discovery Studio Visualizer was used for protein preparation. Analysis of the properties of drug likeliness of the ligands was done via SwissADME online server according to Lipinski’s Rule of Five. Final docking analysis was done through AutoDockVina and Biovia Discovery Studio client 2020. Molecular docking analysis of the ligands Conduritol A, Catechin and Quercetin showed strong binding interaction with both α-amylase and α-glucosidase. The test revealed different binding affinities, hydrogen bond interactions, hydrophobicity, solvent accessibility surface (SAS), root mean square deviation lower bound (RMSD LB) and root mean square deviation upper bound (RMSD UB). Conduritol A was the strongest compound against the protein targets, with its low binding strength, according to the PyRx test and Lipinski 's Rule of Five. The same molecules were further docked, and the interactions were visualized under PyMol Via Biovia Discovery Studio. According to the in silico study, we have found that these natural compounds can inhibit the activities of α-amylase and α-glucosidase which can be promising drugs for the treatment of diabetes after subjecting them to in vitro and in vivo studies.

POSSIBLE CARDIOPROTECTIVE MECHANISM OF ACTION OF DEXRAZOXANE, AND PROBABLE HUMAN TOPOISOMERASE IIβ INHIBITORS: AN IN SILICO ANALYSIS

Objective: The aim of this study was to determine which metabolite plays a role in the cardioprotective effect of dexrazoxane, and also to identify alternative compounds to dexrazoxane since clinical use of dexrazoxane is limited. For this purpose, the interactions of dexrazoxane and its three metabolites (B, C, and ADR-925), as well as the compounds, which reported to be inhibitors for topoisomerase VI (prototype of human DNA topoisomerase II beta), with human DNA topoisomerase II beta were investigated by molecular docking. Afterwards, the theoretical ADMET properties of all these compounds were determined Material and Method: The molecular structures were optimized by Gaussview 05 and Gaussian 03 package programs. AutoDock 4.2 software was used for molecular docking studies and the docking complexes were analyzed in 2D and 3D using the Discovery Studio Client 4.1 program. The pkCSM online program was used to calculate the theoretical ADMET parameters. Result and Discussion: As a result of molecular docking studies, it was determined that the B metabolite of dexrazoxane has a higher binding potential to human DNA topoisomerase II beta compared to both dexrazoxane and its other metabolites. The binding potentials of other compounds reported in the literature to human DNA topoisomerase II beta were radicicol>quinacrine>purpurin>9-Aminoacridine>hexylresorcinol, respectively. The results showed that the B metabolite of dexrazoxane plays an important role in the cardioprotective mechanism of action of dexrazoxane against anthracycline cardiotoxicity. In addition, it has been determined that other compounds, except purpurin, have the potential to cause toxicity.

Anti-Methanogenic Traits of Safflower Oil Compounds Against Methyl-Coenzyme M Reductase Receptor in Equines: An In Silico Docking Analysis

Greenhouse gases emission from livestock is the major concern for the ecosystem. Despite the lower contribution of non-ruminants towards greenhouse gas emission as compared to the ruminants, the emission of methane (CH4) gas from equines is expected to be increased in future due to its increasing population. Thus, it is essential to find or screen potential anti-methanogenic agent in a cost-effective and quicker manner. Considering this, the present investigation was aimed to analyze anti-methanogenic characteristic of bioactive compounds of safflower oil by targeting methanogenesis catalyzing enzyme (Methyl-coenzyme M reductase; MCR) via in silico tool. Initially, a total of 25 compounds associated with safflower oil were selected and their drug-likeness traits were predicted through Lipinski's rule of 5. Of 25 compounds, 9 compounds passed all the parameters of Lipinski's rule of five. These 9 ligands were further submitted for ADME traits analysis using Swiss ADME tool. Results revealed the absence of Lipinski's violation and approval of drug-likeness attributes of methyl tetradecanoate, 3-isopropyl-6-methylenecyclohex-1-ene, trans-2,4-decadienal, cis-6-nonenal, limonene, syringic acids, matairesinol, acacetin, and 2,5-octanedione. Molecular docking analysis was performed for analyzing the affinity between the selected 9 ligands and MCR receptor using FRED v3.2.0 from OpenEye Scientific Software and Discovery Studio client v16.1.0. Results showed maximum binding interaction of acacetin with MCR with the chemguass4 score of -13.35. Other ligands showed comparatively lower binding affinity in the order of matairesinol (-12.43) > methyl tetradecanoate (-9.25) > cis-6-nonenal (-7.88) > syringic acids (-7.73) > limonene (-7.18) > trans-2,4-decadienal (-7.07) > 3-isopropyl-6-methylenecyclohex-1-ene (-7.01) > 2,5-octanedione (-7.0.). In a nutshell, these identified compounds were observed as potential agents to reduce CH4 production from equines by targeting MCR. This in silico study emphasized the role of safflower-associated compounds in developing anti-methanogenic drug for equines in future.

Juvenile hormone mimics with phenyl ether and amide functionality to be insect growth regulators (IGRs): synthesis, characterization, computational and biological study

A series of substituted phenyl ethers derivatives as juvenile hormone (JH) mimics (V1-V8) have been synthesized. Substituted phenoxyacetic acid and amino acid ethyl ester hydrochloride were prepared using NaOH, SOCl2. DCC method has been used for amide linkage. The structure of prepared compounds has been confirmed by Fourier Transform Infra-Red (FT-IR), Electrospray ionization-Mass spectrometry (ESI-MS), Proton and Carbon-13 nuclear magnetic resonance (1H-NMR, 13C-NMR) spectroscopic techniques. Biological efficacy of synthesized analogs has been carried out under laboratory conditions. Galleria mellonella (honey bee pest) has been chosen as testing insect. Juvenile hormone (JH) activity of synthesized compounds has been tested at different concentrations and compared with the standard juvenile hormone analogs (JHAs) pyriproxyfen (M1) and fenoxycarb (M2) against the fifth larval instar of G. mellonella. Compound ethyl 2-[2-(4-methylphenoxy)aminoacetyl]-3-phenyl-propanoate (V6) exhibited better activity among all the synthesized compounds (V1-V8) with LC50 and LC90 values of 0.11 mg/mL and 0.56 mg/mL respectively. Compounds showed insect growth regulating (IGR) activity at lower concentrations. In silico screening of all synthesized compounds with the W-cavity of juvenile hormone-binding protein (JHBP) of insect G. mellonella has been carried out. Chemical reactivity of synthesized series has been studied using DFT/B3LYP/6-311 + G(d,2p) method. Non-toxic behavior of molecules has also been observed from ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) study using discovery studio client 3.0. Communicated by Ramaswamy H. Sarma

COVID-19: docking-based virtual screening and molecular dynamicsstudy to identify potential SARS-CoV-2 spike protein inhibitors from plant-based phenolic compounds.

A novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters into the host cells through an interaction between its surface spike protein (S-protein) and the angiotensin-converting enzyme 2 receptors, leading to coronavirus disease 2019 (COVID-19). Using effective S-protein inhibitors may reduce the virulence of the virus. Molecular docking was performed to evaluate the binding affinity of 97 phenolic compounds (phenolics) with the SARS-CoV-2 S-protein receptor-binding domain (RBD). Molecular dynamics (MD) simulation was carried out to assess the stability of interactions between top-ranked compounds and S-protein RBD. Pharmacokinetics and toxicity of top-ranked inhibitors were also studied. Furthermore, the essential residues involved in ligand binding, based on the degree of each amino acid in the ligand-amino acid interaction (LAI) network for S-protein, were identified. Molecular docking and MD simulations were performed utilizing the AutoDock and Discovery Studio Client version, respectively. The LAI network was analyzed using the Cytoscape software. Pharmacokinetics and toxicity of top-ranked compounds were studied using bioinformatics webservers. It was estimated that nine of the studied phenolics can bind to the SARS-CoV-2 S-protein at the nanomolar scale with a considerable estimated energy of binding (∆G binding Keywords: COVID-19; drug; molecular docking; molecular dynamics; SARS-CoV-2; spike protein.

Analysis of molecular interactions of 8-gingerol compounds in Ginger (Zingiber officinale) as ACE Inhibitor

Background: Hypertension is a disease with increasing characteristics of blood pressure. The ACE gene has a role in the conversion of ATI to ATII in hypertensive conditions. Healing is done by using the 8-gingerol content contained in ginger. The purpose of this study is to analyze the molecular interaction that occurs between 8-gingerol and ACE. Method: ACE model proteins (ID: 3bkk) were obtained from the Bank Data Protein database (PDB) through 8-gingerol ligands (CID: 168114) obtained from the PubChem database. ACE and 8-gingerol were docked by Discovery Study Client 4.1 software. Analysis of amino acid residues, binding energy, Van der Waals forces, and hydrogen bonds formed using Discovery Studio Client 4.1. Results: The interaction between 8-gingerol and ACE showed that there were seven amino acid residues that interacted with 8-gingerol, also found hydrogen bonds, hydrophobic and Van der Waals forces that strengthen and stabilize these bonds. Conclusion: the interaction of 8-ginger with the active side of ACE is determined as an ACE inhibitor, the inhibition is a significant effect on the obstruction of ACE conversion.

Molecular Docking Chlorogenic Acid and Isomer Compound as Cyclooxygenase-2 (COX-2) Inhibitor in Atherosclerosis

Atherosclerosis is an inflammatory disease caused by oxidized LDL. Chloroghenic acid (CGA) is a polyphenol compound and its isomers such as Caffeoylquinic acid (CQA) and Feruloylquinic acid (FQA) can increase the activity of antioxidant activity and can significantly reduce total cholesterol in the blood. Cyclooxygenase (COX) is an enzyme that correlates with the inflammatory process. COX is divided into two isoforms, COX-1 and COX-2. Prostanoid synthesis via the action of cyclooxygenase-2 (COX-2) is a component of the inflammatory response. All prepared compound of Chlorogenic acid (CGA) and its isomer, Caffeolycquinic acid (CQA) and Feruloylquinic acid (FQA) is used for molecular docking by using HEX 8.0.0. Visualization process is done by using Discovery Studio Client 4.1 software. The results showed docking between COX-2 with CGA compounds and its isomers also drug Ibuprofen shows energy binding COX-2 - CGA of -320 kcal / mol, COX-2 - CQA of -298 kcal / mol, COX-2 - FQA of -282 kcal / mol, and COX-2 - Ibuprofen of -230 kcal / mol. The docking results show the CGA compound and its isomers have smaller energy bindings than the drug Ibuprofen. This shows that the CGA compound and its isomers are better than the Ibuprofen drug so that it has the potential as an anti-inflammatory which can be used to prevent the formation of atherosclerosis.

Virtual Inhibition Analysis of Bioactive Compound Brazilin (Caesalpinia sappan L.) Toward Progesterone Receptor or Lonaprisan in Breast Cancer Proliferation

Breast cancer is one of the leading causes of death worldwide. The pathway of breast cancer in KEGG shows that the most effective pathway is through the progesterone receptor (PR). Brazilin is a bioactive compound of secang (Caesalpinia sappan L.) used to inhibit breast cancer through survivin and Bcl-2 pathway but the interaction with PR route is unknown. This research was conducted to determine the virtual interaction between brazilin and PR and its comparison with lonaprisan, so the potential of breast cancer drugs that can overcome through three targets at once with minimal side effects is expected to be known. There are five docking interactions, including the interaction of PR-progesterone, PR-brazilin, PR-brazilin-progesterone, PR-lonaprisan, and PR-lonaprisan-progesterone. Protein and ligand preparation was performed by using Discovery Studio Client 2019 and PyRx 0.8, molecular docking was performed by using Hex 8.0.0 and visualization used Discovery Studio Client 2019. Virtual interaction results shows that lonaprisan has the most stable bond (lowest binding energy), -333.8kJ/mol but when progesterone was docked afterwards the result shows the opposite. Brazilin has a more stable bond compared to lonaprisan with a difference of 2.1kJ/mol and supported by hydrophobic bonds also capable of changing the position of progesterone in binding to PR so that it is estimated that brazilin has the potential as SPRMs, an alternative breast cancer drug to replace lonaprisan. Herbal medicine with brazilin can be estimated to fight breast cancer through 3 targets at once (survivin, Bcl-2, PR).

In-silico Approach for The Prediction of Chlorogenic Acid as PPAR-γ Activator

Coffee is one of the essential crops commonly cultivated in Indonesia. Coffee contains diverse bioactive compounds, which are associated with human health benefits. One of the compounds is Chlorogenic acid, which able to decrease the risk of type 2 diabetes mellitus (T2DM). However, the mechanism of chlorogenic acid toward anti-diabetes still unclear. This study aimed to analyze and investigate the potential role of chlorogenic acid as anti-diabetes through their interaction with Peroxisome proliferator-activated receptor gamma (PPAR-γ) as an enzyme to phosphorylate and regulate the mechanism of T2DM. The physicochemical properties of chlorogenic acid also performed in this study. The PPAR-γ was downloaded from the PDB database, and the chlorogenic acid was retrieved from the PubChem database. The protein and ligand were prepared using the PyRx program and were docked using Hex 8.0.0 software. Discovery Studio client 4.1 software was used to analyze the interaction between chlorogenic acid and PPAR-γ protein. Based on the physicochemical properties, chlorogenic acid is highly permeable to the cell and easily absorbed. Thirteen amino acid residues of PPAR-γ (GLN410, SER394, ASP396, GLY395, GLU407, LEUA401, LEU400, VAL403, LYS373, LYS438, LEU377, LYS434, and GLY437) were identified on the chlorogenic acid-PPAR-γ interaction. Interestingly, the kind of interactions, including hydrophobic interaction, hydrogen bond, and van der Waals, which are supported by the tight interaction. Our study indicated that chlorogenic acid might have anti-diabetes activity through PPAR-γ interaction.&#x0D;

Combination of Curcumin from Curcuma longa and Procyanidin from Tamarindus indica in Inhibiting Cyclooxygenases for Primary Dysmenorrhea Therapy: In silico study

Turmeric (Curcuma longa) and Tamarind (Tamarindus indica) are known for the anti-inflammatory and antioxidant activity. The major bioactive compound found in turmeric is curcumin, and tamarind is procyanidin. Both compounds could reduce prostaglandin concentration, leading to the reduction of primary dysmenorrhea by inhibiting COXs. This study aims to identify the interaction of tamarind and turmeric bioactive compounds as single isolated compound and complex compounds to COXs using in silico as a model study. Proteins and bioactive compounds were obtained from PDB database and Pubchem, respectively. Both proteins and ligands will be prepared using Discovery Studio Client 3.5 and PyRx 0.8. The interaction will be performed by docking using Autodock Vina in PyRx 0.8. It showed that turmeric and tamarind bioactive compounds in single isolated form have potency in inhibiting COX-1/COX-2, and both ligands bind to the catalytic site of proteins. Binding sites are surrounding the binding site of the natural substrate with an efficient binding affinity. In the complex form of turmeric-tamarind, the binding affinity is not as efficient as single compounds. However, its complex form of both compounds provides strong inhibition. This study suggested that complex forms of curcumin and procyanidin can reduce prostaglandin concentration and stabilize protein-ligand interaction lead to healing dysmenorrhea.

Molecular Docking and Dynamics Simulation Analysis of Thymoquinone and Thymol Compounds from Nigella sativa L. that Inhibits P38 Protein: Probable Remedies for Hepatocellular Carcinoma.

Currently, a novel antagonist against p38 is being designed and applied to inhibit hepatocellular carcinoma. Protein-ligand interaction plays a major role in the identification of the possible mechanism for the pharmacological action. The involvement of p38 remains an important target for anticancer drug development as its activation induces apoptosis in hepatoma cells. The aim is to identify the best candidate from the plants of N. sativa which binds with the hepatocellular carcinoma (HCC) targets by computational approach. The reported phytoconstituents such as thymoquinone and thymol present in the plant, N. sativa were docked with the HCC target such as p38. Structures of phytoconstituents were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, p38 was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa, and the compounds were further promoted for molecular docking and MD simulation analysis. The docking results revealed promising inhibitory potential of thymoquinone against p38 with binding energy of -7.67 kcal/mole as compared to its known standard doxorubicin having binding energy of -6.68 kcal/mol respectively. Further, molecular dynamic (MD) simulations for 5ns were conducted for optimization, flexibility prediction, and determination of folded p38 stability. The p38-thymoquinone complex was found to be quite stable with RMSD value of 0.2 nm. Obtained results propose thymoquinone binding energy on the selected targets. Hence, this compound bears outstanding potential against hepatocellular carcinoma and has to be taken up for experimental work against hepatocellular carcinoma.

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.

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. 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. 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. 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. 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.