Highest Docking Score Research Articles

M Protein from Dengue virus oligomerizes to pentameric channel protein: in silico analysis study.

The Dengue virus M protein is a 75 amino acid polypeptide with two helical transmembranes (TM). The TM domain oligomerizes to form an ion channel, facilitating viral release from the host cells. The M protein has a critical role in the virus entry and life cycle, making it a potent drug target. The oligomerization of the monomeric protein was studied using ab initio modeling and molecular dynamics (MD) simulation in an implicit membrane environment. The representative structures obtained showed pentamer as the most stable oligomeric state, resembling an ion channel. Glutamic acid, threonine, serine, tryptophan, alanine, isoleucine form the pore-lining residues of the pentameric channel, conferring an overall negative charge to the channel with approximate length of 51.9 Å. Residue interaction analysis (RIN) for M protein shows that Ala94, Leu95, Ser112, Glu124, and Phe155 are the central hub residues representing the physicochemical interactions between domains. The virtual screening with 165 different ion channel inhibitors from the ion channel library shows monovalent ion channel blockers, namely lumacaftor, glipizide, gliquidone, glisoxepide, and azelnidipine to be the inhibitors with high docking scores. Understanding the three-dimensional structure of M protein will help design therapeutics and vaccines for Dengue infection.

Phytochemicals-based β-amyloid cleaving enzyme-1 and MAO-B inhibitors for the treatment of Alzheimer’s disease: molecular simulations-based predictions

Alzheimer’s disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features. Communicated by Ramaswamy H. Sarma

Exploration of CviR-mediated quorum sensing inhibitors from Cladosporium spp. against Chromobacterium violaceum through computational studies

An opportunistic human pathogenic bacterium, Chromobacterium violaceum resists the potency of most antibiotics by exploiting the quorum sensing system within their community to control virulence factor expression. Therefore, blocking the quorum sensing mechanism could help to treat several infectious caused by this organism. The quorum sensing receptor (CviR) of C. violaceum was used as a model target in the current investigation to identify potentially novel quorum sensing inhibitors from Cladosporium spp. through in silico computational approaches. The molecular docking results confirmed the anti-quorum sensing potential of bioactive compounds from Cladosporium spp. through binding to CviR with varying docking scores between – 5.2 and – 9.5 kcal/mol. Relative to the positive control [Azithromycin (– 7.4 kcal/mol)], the top six metabolites of Cladosporium spp. had higher docking scores and were generally greater than – 8.5 kcal/mol. The thermodynamic stability and binding affinity refinement of top-ranked CviR inhibitors were further studied through a 160 ns molecular dynamic (MD) simulation. The Post-MD simulation analysis confirmed the top-ranked compounds' affinity, stability, and biomolecular interactions with CviR at 50 ns, 100 ns, and 160 ns with Coniochaetone K of the Cladosporium spp. having the highest binding free energy (– 30.87 kcal/mol) and best interactions (two consistent hydrogen bond contact) following the 160 ns simulation. The predicted pharmacokinetics properties of top selected compounds point to their drug likeliness, potentiating their chance as a possible drug candidate. Overall, the top-ranked compounds from Cladosporium spp., especially Coniochaetone K, could be identified as potential C. violaceum CviR inhibitors. The development of these compounds as broad-spectrum antibacterial medicines is thus possible in the future following the completion of further preclinical and clinical research.

Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors.

The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6'-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of -7.526 kcal/mol, -7.438 kcal/mol, and -7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (-6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.

Formulation of multicomponent inclusion complex of cyclodextrin-amino acid with Chrysin: Physicochemical characterization, cell viability and apoptosis assessment in human primary glioblastoma cell line

Chrysin (CR) is a water-insoluble drug reported for different therapeutic effects. The microwave irradiation method was used in this study to create a multicomponent inclusion complex (CR-MC) containing CR (drug) and carrier hydroxyl propyl beta cyclodextrin (HP β CD) and L-arginine (LA). The prepared inclusion complex (CR-MC) was evaluated for dissolution study and results were compared with chrysin physical mixture (CR-PM). Further, the samples were assessed for infra-red (IR), nuclear magnetic resonance (NMR), differential scanning calorimeter (DSC), scanning electron microscope (SEM) and molecular docking. Finally, the cell viability, reactive oxygen species and flow cytometer studies were also assessed to check the potential of the prepared inclusion complex on the human primary glioblastoma cell line (U87-MG cell). The phase solubility findings revealed a stability constant (773 mol L−1) as well as a complexation efficiency of 0.027. The dissolution study displayed a significant increase in CR release from CR-MC (99.03 ± 0.39%) > CR-PM (70.58 ± 1.16%) > pure CR (35.29 ± 1.55%). NMR and IR spectral data revealed no interaction between CR and carriers. SEM and DSC study results revealed the conversion into amorphous form. The molecular docking results illustrated a high docking score, which supports the findings of complex formation. The cell viability, reactive oxygen species, and flow cytometry studies results showed enhanced activity from CR-MC against the tested human primary glioblastoma cell line. From the results it has been observed that chrysin solubility significantly increased after complexation and there in vitro activity also enhanced against cancer cell line.

Anti‐Epileptic Drug‐Lipid Conjugates for Delivery to the Brain: In Silico ADMET Prediction, Molecular Docking and Molecular Dynamics Simulations

AbstractNeurological disease epilepsy has unfortunately become widespread, affecting around 50 million individuals worldwide. Levetiracetam (LVM) is a newer‐generation drug but its hydrophilic nature restricts its BBB (blood‐brain barrier) permeability. This results in increased dose, dosing frequency, and side effects. Therefore, different lipid‐drug conjugates (LDCs) were studied to identify the compound capable of BBB permeation. The binding potential of LDCs with human brain fatty‐acid binding protein (HBFABP) (PDB id: 1FDQ) was determined by molecular docking through extra‐precision (XP) algorithm of Maestro. In simulations, OPLS3e force field was applied. The ADMET prediction was performed by QikProp and pkCSM web tool. The selected compounds were investigated for LDC‐BFABP complex stability through molecular dynamics (MD) study. All compounds indicated good pharmacokinetic profiles. The LVM‐palmitic acid and LVM‐stearic acid conjugates indicated higher docking scores and greater stability than LVM alone. Thus, they can be selected as potential molecules for further drug development to obtain clinically useful LDC for treatment of CNS disorder.

Exploration on learning molecular docking with deep learning models

A deep learning‐powered VS approach combined with two free docking programs are proposed and evaluated for screening an ultra‐large compound library to obtain diverse potential active compounds rapidly and efficiently. We found that it is a practical and transferable strategy to significantly reduce computational cost.BackgroundMolecular docking‐based virtual screening (VS) aims to choose ligands with potential pharmacological activities from millions or even billions of molecules. This process could significantly cut down the number of compounds that need to be experimentally tested. However, during the docking calculation, many molecules have low affinity for a particular protein target, which waste a lot of computational resources.MethodsWe implemented a fast and practical molecular screening approach called DL‐DockVS (deep learning dock virtual screening) by using deep learning models (regression and classification models) to learn the outcomes of pipelined docking programs step‐by‐step.ResultsIn this study, we showed that this approach could successfully weed out compounds with poor docking scores while keeping compounds with potentially high docking scores against 10 DUD‐E protein targets. A self‐built dataset of about 1.9 million molecules was used to further verify DL‐DockVS, yielding good results in terms of recall rate, active compounds enrichment factor and runtime speed.ConclusionsWe comprehensively evaluate the practicality and effectiveness of DL‐DockVS against 10 protein targets. Due to the improvements of runtime and maintained success rate, it would be a useful and promising approach to screen ultra‐large compound libraries in the age of big data. It is also very convenient for researchers to make a well‐trained model of one specific target for predicting other chemical libraries and high docking‐score molecules without docking computation again.

Marine brown algae (Sargassum wightii) derived 9-hydroxyhexadecanoic acid: A promising inhibitor of α-amylase and α-glucosidase with mechanistic insights from molecular docking and its non-target toxicity analysis

Jeopardized glucose hemostasis leads to cronic metaboic disorder like Diabetes mellitus and it is predicted to occur in ∼700 million people in the coming 20 years. Our study aims to isolate Palmitic acid (C16H32O3), 9-Hydroxyhexadecanoic acid metabolite from Sargassum wightii to inhibit alpha-amylase and alpha-glucosidase to reduce postprandial hyperglycemia and decline the risk of diabetes. High docking score of palmitic acid with both α-amylase and α-glucosidase is observed in in-silico molecular docking analysis, in comparison to commercially available drug acarbose. The three hydrogen bond in palmitic acid interacts with the important amino acids like Arg195, Lys200 and Asp300 in Glide XP docking mode for alpha-amylase. For α-glucosidase, quantum-polarized ligand docking (QPLD) was used with similar three hydrogen bond interactions. Both docking studies showed significant binding interaction of palmitic acid with α-amylase (−5.66 and −5.14 (Kcal/mol)) and with α-glucosidase (−4.52 and −3.51(Kcal/mol)) with respect to the standard, acarbose docking score. The bioactive palmitic acid isolated from the brown alga, Sargassum wightii is already seen to inhibit digestive enzyme with non-target property in Artemia nauplii and zebra fish embryos. Further studies are required to investigate its role in in vivo antidiabetic effects due to its non-toxic and digestive enzyme inhibitory properties. It can be recommended in additional pharmaceutical studies to develop novel therapeutics to manage diabetes mellitus.

In silico screening-based discovery of benzamide derivatives as inhibitors of Rho-associated kinase-1 (ROCK1)

As a pivotal node in modulating various cell behaviors, Rho-associated kinase-1 (ROCK1) has attracted significant attention as a promising therapeutic target in a variety of diseases. Benzamide has been widely reported as a ROCK1 inhibitors in recent years. To better understand its pharmacological properties and to explore its potential inhibitors, a series of ROCK1 inhibitors derived from N-methyl-4-(4-pyrazolidinyl) benzamides (MPBs) were investigated by using three-dimensional quantitative structure-activity relationship (3D-QSAR) models, pharmacophore models, molecular docking, and molecular dynamics (MD) simulation. The comparative Molecular Field Analysis (CoMFA) model (q2 = 0.616, R2 = 0.972, ONC = 4, and r2 pred = 0.983) and the best Comparative Molecular Similarity Indices Analysis (CoMSIA) model (q2 = 0.740, R2 = 0.982, ONC = 6, and r2 pred = 0.824) exhibited reliable predictability with satisfactory validation parameters. In the subsequent virtual screening, VS03 and VS05 were identified to have superior predicted activities and higher docking scores, meanwhile they demonstrated to be reasonably stable in the binding pocket through MD simulations. These results provide a significant theoretical direction for the rational design and development of novel ROCK1 inhibitors. Communicated by Ramaswamy H. Sarma

Investigation of Iminosugars as Antiviral Agents against SARS-CoV-2 Main Protease: Inhibitor Design and Optimization, Molecular Docking, and Molecular Dynamics Studies to Explore Potential Inhibitory Effect of 1-Deoxynojirmycin Series.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses an enormous challenge to human health and economy at a global level. According to WHO's latest data, till now, there have been a total of 641,435,884 confirmed cases of COVID-19, and the associated deaths are 6,621,060. Though few vaccinations have been approved for emergency usage, antiviral medications for long-term therapeutics are still being sought. The current research seeks to identify the inhibitory effect of iminosugars, particularly 1-deoxynojirmycin (IDNJ) series, against SARS-CoV-2 main protease (SARS-CoV2-Mpro) using an inhibitor optimization approach for 1DNJ series. The aim of this study was to investigate the inhibitory effect of iminosugars, specifically 1-deoxynojirmycin (1-DNJ) derivatives, on SARS-CoV-2 main protease (Mpro) as it plays a vital role in viral propagation and transcription and is shaped like a heart. The main objective of this study was to find the possibility of 1-DNJ derivatives being potent inhibitors against SARS CoV2 Mpro. This study was focused on finding the most probable conformation in which DNJ derivatives could bind to Mpro. Another objective was to obtain molecular-level details by getting insights into stable interactions formed between the ligand and receptor. In silico molecular mechanics (MM) based techniques were employed to identify the best-docked inhibitors using molecular docking, and complexes that showed stable interactions were further subjected to 200 ns of molecular dynamics (MD) simulations to check the stability of ligand into the binding pocket of SARS-CoV2-Mpro. The inhibitors that formed stable complexes were further tested for their ADME properties in order to check the pharmacokinetic parameters as well as their therapeutic importance. Docking was performed on 29 compounds from two different series against SARS-CoV-2 main protease, Mpro (PDB ID: 6LZE). Twelve compounds were found to have high docking scores and better interactions with the active site of Mpro, as compared to the co-crystallized ligand. Furthermore, the three highest-scoring docked compounds (17a, 7, and 8) depicted strong and stable complex formation, throughout the 200 ns molecular dynamics simulation, by analyzing the binding energy (MM/GBSA). The molecules were discovered to form stable interactions with conserved active-site residues, which play an important role in demonstrating activity in structure-based drug design. The ADMET analysis was performed using Qikprop, and the proposed stable derivatives passed all of the needed drug discovery standards, potentially inhibiting the Mpro of SARS-CoV-2. The present findings confer opportunities for compounds 17a, 7, and 8 that could be developed as new therapeutic agents against COVID-19. These compounds are suggested on the basis of pharmacokinetic parameters as well as therapeutic importance and hence could be tested in-vitro.

Identification of a small chemical as a lysosomal calcium mobilizer and characterization of its ability to inhibit autophagy and viral infection.

We previously identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as one of the cyclic adenosine diphosphoribose (cADPR)'s binding proteins and found that GAPDH participates in cADPR-mediated Ca2+ release from endoplasmic reticulum via ryanodine receptors (RyRs). Here, we aimed to chemically synthesise and pharmacologically characterise novel cADPR analogues. Based on the simulated cADPR-GAPDH complex structure, we performed the structure-based drug screening, identified several small chemicals with high docking scores to cADPR's binding pocket in GAPDH and showed that two of these compounds, C244 and C346, are potential cADPR antagonists. We further synthesised several analogues of C346 and found that its analogue, G42, also mobilised Ca2+ release from lysosomes. G42 alkalised lysosomal pH and inhibited autophagosome-lysosome fusion. Moreover, G42 markedly inhibited Zika virus (ZIKV, a flavivirus) or murine hepatitis virus (MHV, a β-coronavirus) infections of host cells. These results suggest that G42 inhibits virus infection, likely by triggering lysosomal Ca2+ mobilisation and inhibiting autophagy.

Exploring potential Plasmodium kinase inhibitors: a combined docking, MD and QSAR studies

Malaria is a disease caused mostly by Plasmodium falciparum, affects millions of people each year. The kinases are validated targets for malaria infection. In this study, we investigate for real and hypothetical compounds that can inhibit cyclic guanosine monophosphate (CGMP)-dependent protein kinase using molecular docking via combined similarity analysis, molecular dynamics simulations, quantitative structure activity relationship (QSAR). Using Tanimoto similarity scores, ∼8.4 million compounds were screened. Compounds that have at least 70% similarity are used in further analysis. These compounds are assessed by means of docking, MMBPSA, MMGBSA and ANI_LIE. Based on consensus of different free energy methods and docking we revealed two potential inhibitors that can be useful for treatment of malaria. Apart from screening of real compounds, we have also selected the 10 most plausible hypothetical compounds by performing QSAR. By QSAR proposed pharmacophores, we generated over 247 hypothetical compounds and among them 19 molecules with lower QSAR predicted IC50 values and high docking scores were selected for further analysis. We selected the top 10 inhibitor candidates and performed MD simulations for free energy calculations like the protocol applied for real compounds. According to the free energy calculations, we suggest 2 real (C34H29F5N8O4S and C30H27F2N7O2S2, PubChem IDs: 140564801 and 89035196, respectively) and 2 hypothetical (C23H27FN6O2S, MOL3 and C23H25FN6O2S, MOL4) compounds that can be effective inhibitors against the protein kinase of Plasmodium falciparum. Communicated by Ramaswamy H. Sarma

Supervised screening of Tecovirimat-like compounds as potential inhibitors for the monkeypox virus E8L protein

Monkeypox virus (MPXV) is a budding public health threat worldwide, and there lacks a personalized drug availability to treat MPXV infections. Tecovirimat, an antiviral drug against pox viruses, is recently confirmed to be effective against the MPXV in vitro using nanomolar concentrations. Therefore, the current study considers Tecovirimat as a reference compound for a machine learning-based guided screening to scan bioactive compounds from the DrugBank with similar chemical features or moieties as the Tecovirimat to inhibit the MPXV E8L surface binding protein. We used AlphaFold2 to model the E8L’s 3D structure, followed by the conformational activity investigation of shortlisted drugs through computational structural biology approaches, including molecular docking and molecular dynamics simulations. As a result, we have shortlisted five drugs named ABX-1431, Alflutinib, Avacopan, Caspitant, and Darapalib that effectively engage the MPXV surface binding protein. Furthermore, the affinity of the proposed drugs is relatively higher than the Tecovirimat by having higher docking scores, establishing more hydrogen and hydrophobic bonds, engaging key residues in the target’s structure, and exhibiting stable molecular dynamics. Communicated by Ramaswamy H. Sarma

Investigation of molecular mechanisms of Ulmus davidiana against gastric cancer: A network pharmacology study incorporating gene expression data and molecular docking analysis

Ulmus davidiana (UD), has long been utilized in traditional medicine to treat various diseases, particularly gastric cancer (GC). However, the molecular mechanism behind its health-protective effect has yet to be clarified. An extensive literature search was conducted to collect all reported phytochemicals of the plant, which were then filtered for druglike properties. SwissTargetPrediction was utilized to predict targets for phytochemicals and functional enrichment of targets was performed for GO, pathways, and diseases. A network pharmacology approach was used to investigate all possible targets and targets specifically associated with GC. The expression of target genes was also studied for their expression in the TCGA patient GC dataset from TCGA through GEPIA 2.0. Cytoscape and STRING were used for network construction and analysis, while core targets and filtered phytochemicals were employed for molecular docking. In total, 396 targets for screened compounds, of which 242 targets were associated with GC. Among these, 87 targets were differentially expressed in GC. Several highly differentially expressed genes (MMP7, TOP2A, CCNB2, MMP12, and CCNB2) were found to be strongly associated with gastric cancer. Target enrichment categories were correlated with the known bioactivities of UD such as antioxidant, anti-inflammatory, and anticancer properties. Cancer and neurological complications-related diseases were prevalent in the associated disease network. The interferon-gamma signaling pathway was identified as the most enriched pathway for gastric cancer targets (GT). CCKR signaling was found to be the most connected pathway in the GC network. Core targets (HSP90AA1, STAT3, SRC, ESR1, and EGFR) were determined through protein-protein-interaction network analysis. Molecular docking revealed phytochemicals (torilin, 1-hydroxytorilin, and butyl alpha-D-fructofuranoside) with high docking scores and strong interactions with core targets. The key findings of the study, including phytochemicals, targets, and pathways, are suggested for further validation.

Structure-guided Design and Optimization of small Molecules as Pancreatic Lipase Inhibitors using Pharmacophore, 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation Studies.

Obesity has now become a global issue due to the increase in the population of obese people. It also substantially impacts the individual's social, financial, and psychological well-being, which may contribute to depression. Being overweight induces many metabolic and chronic disorders, urging many researchers to focus on developing the drug for obesity treatment. Pancreatic lipase inhibitors and natural product/compound-derived pancreatic lipase inhibitors have recently received much attention because of their structural variety and low toxicity. This study aimed to build pharmacophores and QSAR for analyzing the necessary structure of pancreatic lipase inhibitors and designing new molecules with the best activity. Ligand-based pharmacophore modeling and Atom-Based 3D-QSAR were carried out using the PHASE module of Schrodinger to determine the critical structural properties necessary for pancreatic lipase (PL) inhibitory activity. A total of 157 phytoconstituents and a standard drug, orlistat, were selected for the present study. Considering the important features for pancreatic lipase inhibition, 15 new molecules were designed and subjected to molecular docking studies and molecular dynamics simulations. The activity of designed molecules was predicted using the Atom- Based QSAR tool of the PHASE module. The top docked score molecule is structure-7 with a docking score of -6.094 Kcal/mol, whereas the docking score of orlistat and tristin is -3.80Kcal/mol and -5.63Kcal/mol, respectively. The designed molecules have a high docking score and good stability, are in the desirable ADME range and are derived from natural products, so they might be used as lead molecules for anti-obesity drug development.

DFT and In-silico Investigations, along with In-vitro Antitumor and Antimicrobial Assessments of Pharmacological Molecules.

Molecules bearing an active methylene bridge are one of the most fruitful and remarkable precursors that have been incorporated into the synthetic strategy of an assortment of bioactive compounds. The reactive methylene derivatives have been endowed with multiple reactions, which target biological and medicinal applications and result from their structural diversity and discrete reactivity. The present report endeavors to synthesize, characterize, and in-vitro evaluate several novel propanoic acids, coumarin, and pyrazole derivatives as antimicrobial and antiproliferative agents. The in-silico molecular docking, physicochemical, pharmacokinetic/ADMET, bioactivity, and drug-likeness predictions were conducted for all the synthesized compounds. The highest docking score is -9.9 and -8.3 kcal/mol, respectively, for compound 9 (azocoumarin) and 13 (acrylic acid derivative) with the target proteins E. coli topoisomerase II, DNA gyrase subunit B and PI3K p110α domain, respectively. Moreover, this study predicts the synthesized molecules that may inhibit the novel COVID-19, obtained through virtual screenings only, where compounds 9, 13, 14, 17, and 19 came to the limelight with good docking scores i.e., more than -8 Kcal/mol. Safety profiling of the most potent compound 9 was utilized against normal cell lines and the hemolytic effect on RBCs. The in-silico ADMET studies of the synthesized compounds revealed moderate to good -likeness, high gastro intestinal (GI) absorption, and inhibiting the Cytochrome CYP2C19 and CYP2C9 and all the derivatives possess non-cancerous nature. The in-vitro screening demonstrated that several of the novel molecules are promising drug candidates. The density functional theory (DFT) theoretical calculations were performed to calculate the energy levels of the FMOs and their energy gaps, dipolemoment, andmolecular electrostatic potential. Such parameters, along with the physicochemical parameters, could be a good tool to confirm biological activity.

VEGFR2 Mimicking Peptide Inhibits the Proliferation of Human Umbilical Vein Endothelial Cells (Huvecs) by Blocking VEGF.

A variety of key human physiological processes rely on angiogenesis, ranging from reproduction and fetal growth to wound healing and tissue repair. Furthermore, this process significantly contributes to tumor progression, invasion, and metastasis. As the strongest inducer of angiogenesis, Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) are targets of therapeutic research for blocking pathological angiogenesis. Preventing the interaction between VEGF and VEGFR2 by a peptide is a promising strategy for developing antiangiogenic drug candidates. This study was aimed at designing and evaluating VEGF-targeting peptides using in silico and in vitro techniques. The VEGF binding site of VEGFR2 was considered a basis for peptide design. The interaction of VEGF and all three peptides derived from VEGFR2 were analyzed using ClusPro tools. In a complex with VEGF, the peptide with a higher docking score was evaluated to confirm its stability using molecular dynamics (MD) simulation. The gene coding for the selected peptide was cloned and expressed in E. coli BL21. The bacterial cells were cultured on a large scale, and the expressed recombinant peptide was purified using Ni-NTA chromatography. Refolding of the denatured peptide was carried out by the stepwise removal of the denaturant. The reactivity of peptides was confirmed using western blotting and enzyme-linked immunosorbent assay (ELISA) assays. Finally, the inhibition potency of the peptide on human umbilical vein endothelial cells was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay. Among three peptides, the peptide with the best docking pose and the highest affinity for VEGF was selected for further studies. Then the stability of the peptide was confirmed over the 100 ns MD simulation. After in silico analyses, the selected peptide was presented for in vitro analysis. Expression of the selected peptide in E. coli BL21 resulted in a pure peptide with a yield of approximately 200 μg/ml. Analysis by ELISA revealed the high reactivity of the peptide with VEGF. Western blot analysis confirmed the specific reactivity of selected peptides with VEGF. The MTT assay revealed the growth inhibitory effect of the peptide on human umbilical vein endothelial cells with an IC50 value of 247.8 μM. In summary, the selected peptide demonstrated a promising inhibitory effect on human umbilical vein endothelial cells that could be a valuable anti-angiogenic candidate for further assessment. Additionally, these in silico and in vitro data provide new insights into peptide design and engineering.

Synthesis, In-Silico, In Vitro and DFT Assessments of Substituted Imidazopyridine Derivatives as Potential Antimalarials Targeting Hemoglobin Degradation Pathway

Malaria is a serious illness transmitted through the bite of an infected mosquito, which is caused by a type of parasite called plasmodium and can be fatal if left untreated. Thus, newer antimalarials with unique mode of actions are encouraged. Fused pyridines have been vastly reported for numerous pharmacological activities including but not limited to analgesics, antitubercular, antifungal, antibacterial and antiapoptotic agents. In a current study, a series of substituted Imidazo[1,2-a]pyridine-3-carboxamides (IMPCs) (SM-IMP-01-13) along with some hydrazides (DA-01-DA-02) were synthesized and characterized by Fourier-transform infrared spectroscopy (FTIR), 1H-/[Formula: see text]C-NMR (proton/carbon nuclear magnetic resonance), elemental analyses and mass spectra. These synthesized analogies were subjected for in vitro biological activities such as Brine Shrimp lethality (BSL), and assay of [Formula: see text]-hematin formation inhibitions. The BSL assay results suggested that compounds, SM-IMP-09, SM-IMP-05 were found to be less toxic and they also had comparable toxicity as of 5-Flurouracil (control) ((e.g., at 10 [Formula: see text]g/ml: 20% deaths of nauplii). Derivatives SM-IMP-02, and DA-05 inhibited [Formula: see text]-hematin formation: IC[Formula: see text]: 1.849 and 0.042 [Formula: see text]M, respectively). Our molecular docking analysis on plasmodial cysteine protease falcipain-2 indicated that compound DA-05 (–9.993 kcal/mol) had highest docking score and it was comparable to standard Chloroquine (–7.673 kcal/mol). The most active molecule, DA-05 was also retained with lower HOMO–LUMO energy gap as 3.36 eV. Further, we have also analyzed MEP, and other global reactivity indexes for all IMPCs using DFT. Finally, our in-silico pharmacokinetic analysis suggested that all compounds were having good% human oral absorption values ([Formula: see text]100%), good Caco-2 cell permeabilities (>1600 nm/s), and non- carcinogenic profiles.

Development of novel bosentan analogues as endothelin receptor antagonists for pulmonary arterial hypertension

Since decades, bosentan has been in use for the treatment of pulmonary arterial hypertension (PAH). However, chronic exposure to bosentan leads to the development of resistance, tolerance, and serious adverse effects that have restricted its usage in clinical practices. To surmount these limitations, some new bosentan derivatives have been synthesized and evaluated for their therapeutic efficacy in PAH. Molecular docking analyses of all the synthesized derivatives were carried out using the endothelin (ET) receptor. In addition, the inhibitory ability of synthesized derivatives was determined in in vitro assay employing an ET-1 human ELISA kit. Among the synthesized derivatives, three derivatives namely 17d, 16j, and 16h with higher docking scores and lower IC50 values were selected for determination of the magnitude of the binding force between the derivative and ET receptor using molecular dynamics (MD) simulations study. Further, these derivatives were subjected to in vivo studies using monocrotaline (MCT) induced PAH in rat model. Results of in vivo studies inferred that the derivatives exhibit impressive ability to reduce PAH. Besides, its protective role was also evidenced in hemodynamic and right ventricular hypertrophy analyses, histological analysis, cardiac biomarkers, hypoxia-inducible factor 1 alpha (HIF1α) levels, and biochemical studies. Furthermore, gene quantification by quantitative RT-PCR and Western blot analysis was also performed to examine its effect on the expression of key proteins in PAH.Notably, amongst three, derivative 16h exhibited the most encouraging results in molecular docking analysis, in vitro, in vivo, histopathological, biochemical, protein expression, and MD studies. Besides, derivative 16h also showed impressive pharmacokinetic features in ADMET analysis.In conclusion, derivative 16 h could act as a reliable ET receptor antagonist and requires further exploration to attain its therapeutic utility in PAH management.

Emodin and aloe-emodin, two potential molecules in regulating cell migration of skin cells through the MAP kinase pathway and affecting Caenorhabditis elegans thermotolerance

BackgroundEmodin and aloe-emodin are two anthraquinones having positive effects in wound healing. However, their mechanism of action of wound healing is not fully understood. The MAP kinase family, which plays an active role in wound healing, is a well-characterized large family of serine/threonine kinases and regulates processes such as proliferation, oncogenesis, differentiation, and inflammation in the cell. The aim of this study is to comparatively elucidate the mechanisms of action of emodin and aloe-emodin, which are potential agents in wound healing.MethodsThe mechanism of the effects of emodin and aloe-emodin on cell viability and cell migration was examined using the human skin fibroblast (CCD-1079Sk) cell line. The gene expression levels of the MAP kinases (JNK, P38, ERK) in the skin fibroblast cells along with a molecular docking study analyzing their interaction potential were evaluated. Furthermore, the molecules’ effects on the lifespan of Caenorhabditis elegans were studied.ResultsEmodin and aloe-emodin inhibited the ATP content of the cells in a concentration dependent manner and accelerated cell migration at the lower concentrations while inhibiting cell migration in the higher concentration treatment groups. The expressions of JNK and P38 were upregulated at the low concentrations and downregulated at the higher concentrations. The molecular docking studies of the molecules gave high docking scores indicating their interaction potential with JNK and P38. C. elegans lifespan under heat stress was observed longer after 75 µM emodin and was significantly reduced after 150 µM aloe-emodin treatment.ConclusionAloe-emodin was found to be more potent on cell viability, cell migration, gene expression levels of the MAP kinases in healthy fibroblastic skin cells, and on the lifespan of C. elegans. This study reveals the functional effects and the biological factors that interact in the wound healing process of emodin and aloe-emodin, and give a possible treatment alternative to shorten the duration of wound care.