Structure-based virtual screening of plant-derived natural compounds as potential PPARα agonists for the treatment of dyslipidemia

MedPharmRes ◽  
2021 ◽  
Vol 5 (4) ◽  
pp. 34-45
Author(s):  
Phuong Thuy Viet Nguyen ◽  
Truong Le Quang Vo ◽  
Thao Anh Nguyen ◽  
Phuong Ngoc Khanh Ho ◽  
Bao Hoang Gia Nguyen
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Metabolic Pathways ◽  
Hydrophobic Interactions ◽  
Stevia Rebaudiana ◽  
Natural Compounds ◽  
Modern World ◽  
Binding Affinities ◽  
Stemona Tuberosa ◽  
Key Residues

Background: Nowadays, metabolic disorders such as dyslipidemia have become serious health problems in the modern world. PPARs are regulators of numberous metabolic pathways, hence there has been a huge increase in the development and use of the PPARs agonists, especially PPARα agonists as main therapeutic of dyslipidemia. Objectives: The study aimed to explore potential plant-derived natural compounds as PPARα agonist agent for drug discovery of dyslipidemia. Methods: Structure-based virtual screening through molecular docking was conducted for 142 bioactive compounds from 29 medicinal plants on the main binding site of PPARα (PDB ID: 5HYK). Binding affinities and binding interactions between the ligands and PPARα were investigated. Results: Screening results showed that 34 compounds had strong binding affinities into the PPARα (binding affinities of less than -8.0 kcal.mol-1), including 20 flavonoid, 4 terpenoid and 10 alkaloid compounds. Flavonoid was found as the best group which fitted well in the binding site of the PPARα. Top compounds were identified, including formononetin from Thermopsis alterniflora (-10.2 kcal.mol-1), diosmetin from Musa spp. (-10.1 kcal.mol-1), luteolin from Elsholtzia ciliate (-9.9 kcal.mol-1); steviol from Stevia rebaudiana (-9.4 kcal.mol-1); and tuberocrooline from Stemona tuberosa (-10.5 kcal.mol-1), respectively. These compounds showed the potential agonistic activities due to forming the hydrogen bonds as well as hydrophobic interactions with four key residues of the receptor such as Ser280, Tyr314, His440 and Tyr464. Conclusions: These potential natural compounds may provide useful information in the drug design and discovery for anti-dyslipidemia agents.

scholarly journals High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Non-Covalent Inhibitor

2021 ◽  
Author(s):  
Austin Clyde ◽  
Stephanie Galanie ◽  
Daniel W. Kneller ◽  
Heng Ma ◽  
Yadu Babuji ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
High Throughput ◽  
Hydrophobic Interactions ◽  
Md Simulations ◽  
X Ray ◽  
X Ray Crystallography ◽  
Biochemical Assays ◽  
Main Protease ◽  
High Throughput Virtual Screening

Despite the recent availability of vaccines against the acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the search for inhibitory therapeutic agents has assumed importance especially in the context of emerging new viral variants. In this paper, we describe the discovery of a novel non-covalent small-molecule inhibitor, MCULE-5948770040, that binds to and inhibits the SARS-Cov-2 main protease (Mpro) by employing a scalable high throughput virtual screening (HTVS) framework and a targeted compound library of over 6.5 million molecules that could be readily ordered and purchased. Our HTVS framework leverages the U.S. supercomputing infrastructure achieving nearly 91% resource utilization and nearly 126 million docking calculations per hour. Downstream biochemical assays validate this Mpro inhibitor with an inhibition constant (Ki) of 2.9 µM [95% CI 2.2, 4.0]. Further, using room-temperature X-ray crystallography, we show that MCULE-5948770040 binds to a cleft in the primary binding site of Mpro forming stable hydrogen bond and hydrophobic interactions. We then used multiple µs-timescale molecular dynamics (MD) simulations, and machine learning (ML) techniques to elucidate how the bound ligand alters the conformational states accessed by Mpro, involving motions both proximal and distal to the binding site. Together, our results demonstrate how MCULE-5948770040 inhibits Mpro and offers a springboard for further therapeutic design. Significance Statement The ongoing novel coronavirus pandemic (COVID-19) has prompted a global race towards finding effective therapeutics that can target the various viral proteins. Despite many virtual screening campaigns in development, the discovery of validated inhibitors for SARS-CoV-2 protein targets has been limited. We discover a novel inhibitor against the SARS-CoV-2 main protease. Our integrated platform applies downstream biochemical assays, X-ray crystallography, and atomistic simulations to obtain a comprehensive characterization of its inhibitory mechanism. Inhibiting Mpro can lead to significant biomedical advances in targeting SARS-CoV-2 treatment, as it plays a crucial role in viral replication.

Study of AMP-Activated Protein Kinase Agonists by Structure-Based Drug Designing

2009 ◽  
Vol 79-82 ◽  
pp. 2187-2190 ◽  
Author(s):  
Yea Huey Chang ◽  
Tin Yun Ho ◽  
Chieh Hsi Wu ◽  
Chien Yu Chen ◽  
Hung Jin Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Crystal Structure ◽  
Protein Kinase ◽  
Virtual Screening ◽  
Homology Modeling ◽  
Binding Site ◽  
X Ray ◽  
Drug Designing ◽  
Key Residues ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a metabolite- sensed protein kinase in various eukaryotes. The activated AMPK regulates important proteins which cause diabetes, obesity, metabolic aberrant, and also breast cancer. In this study, the yeast AMPK structure was used as a template to model the human AMPK structure. By homology modeling, the reliable AMPK structure was built, and the active binding site was defined corresponding to X-ray crystal structure of yeast AMPK By virtual screening the database., All the potent ligands had the H-bond interaction in the key residues, same as the control. Thus, we suggested the phenylamide derivates might be the potent AMPK agonists.

Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules

2020 ◽  
Vol 21 (2) ◽  
pp. 117-130 ◽  
Author(s):  
Mohammad J. Hosen ◽  
Mahmudul Hasan ◽  
Sourav Chakraborty ◽  
Ruhshan A. Abir ◽  
Abdullah Zubaer ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Glucose Transporter ◽  
Substrate Binding ◽  
Mutation Screening ◽  
Homology Model ◽  
Connective Tissue Disorder ◽  
Crystallographic Structure ◽  
Substrate Binding Site

Objectives: The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes the facilitative glucose transporter GLUT10. The molecules transported by and interacting with GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the substrate binding site of GLUT10 and the molecules interacting with this site. Methods: As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics investigation were employed. Results and Discussion: Blind docking of nine reported potential in vitro substrates with this 3D homology model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437, TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520, SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database (HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10, which were found to be involved directly or partially in ATS progression or different arterial disorders. Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p. Glu437Lys) is located in the predicted substrate binding site region. Conclusion: Virtual screening expands the possibility to explore more compounds that can interact with GLUT10 and may aid in understanding the mechanisms leading to ATS.

Machine Learning-based Virtual Screening Strategy Reveals Some Natural Compounds As Potential PAK4 Inhibitors In Triple Negative Breast Cancer

2020 ◽  
Vol 18 ◽  
Author(s):  
Opeyemi Iwaloye ◽  
Olusola Olalekan Elekofehinti ◽  
Babatomiwa Kikiowo ◽  
Emmanuel Ayo Oluwarotimi ◽  
Toyin Mary Fadipe
Keyword(s):  
Breast Cancer ◽  
Virtual Screening ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Binding Free Energy ◽  
Natural Compounds ◽  
Energy Calculation ◽  
Reference Drug ◽  
Predictive Quality

Background: P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many cancers, especially in the progression of Triple Negative Breast Cancer (TNBC). The present study was aimed at designing some potential drug candidates as PAK4 inhibitors for breast cancer therapy. Objective: This study aimed to finding novel inhibitors of PAK4 from natural compounds using computational approach. Methods: An e-pharmacophore model was developed from docked PAK4-coligand complex and used to screen over a thousand natural compounds downloaded from BIOFACQUIM and NPASS databases to match a minimum of 5 sites for selected (ADDDHRR) hypothesis. The robustness of the virtual screening method was accessed by well-established methods including EF, ROC, BEDROC, AUAC, and the RIE. Compounds with fitness score greater than one were filtered by applying molecular docking (HTVS, SP, XP and Induced fit docking) and ADME prediction. Using Machine learningbased approach QSAR model was generated using Automated QSAR. The computed top model kpls_des_17 (R2= 0.8028, RMSE = 0.4884 and Q2 = 0.7661) was used to predict the pIC50 of the lead compounds. Internal and external validations were accessed to determine the predictive quality of the model. Finally the binding free energy calculation was computed. Results: The robustness/predictive quality of the models were affirmed. The hits had better binding affinity than the reference drug and interacted with key amino acids for PAK4 inhibition. Overall, the present analysis yielded three potential inhibitors that are predicted to bind with PAK4 better than reference drug tamoxifen. The three potent novel inhibitors vitexin, emodin and ziganein recorded IFD score of -621.97 kcal/mol, -616.31 kcal/mol and -614.95 kcal/mol, respectively while showing moderation for ADME properties and inhibition constant. Conclusion: It is expected that the findings reported in this study may provide insight for designing effective and less toxic PAK4 inhibitors for triple negative breast cancer.

scholarly journals Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Structural Characteristics ◽  
Natural Compounds ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Anticancer Activities ◽  
Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

scholarly journals Mitigating the Adverse Effects of Polychlorinated Biphenyl Derivatives on Estrogenic Activity via Molecular Modification Techniques

2021 ◽  
Vol 18 (9) ◽  
pp. 4999
Author(s):  
Wei He ◽  
Wenhui Zhang ◽  
Zhenhua Chu ◽  
Yu Li
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Hydrophobic Interaction ◽  
Oestrogen Receptor ◽  
Polychlorinated Biphenyl ◽  
Hydrophobic Interactions ◽  
Estrogenic Activity ◽  
Average Distance ◽  
Amino Acid Residues ◽  
Hydrophobic Amino Acid

The aim of this paper is to explore the mechanism of the change in oestrogenic activity of PCBs molecules before and after modification by designing new PCBs derivatives in combination with molecular docking techniques through the constructed model of oestrogenic activity of PCBs molecules. We found that the weakened hydrophobic interaction between the hydrophobic amino acid residues and hydrophobic substituents at the binding site of PCB derivatives and human oestrogen receptor alpha (hERα) was the main reason for the weakened binding force and reduced anti-oestrogenic activity. It was consistent with the information that the hydrophobic field displayed by the 3D contour maps in the constructed oestrogen activity CoMSIA model was one of the main influencing force fields. The hydrophobic interaction between PCB derivatives and oestrogen-active receptors was negatively correlated with the average distance between hydrophobic substituents and hydrophobic amino acid residues at the hERα-binding site, and positively correlated with the number of hydrophobic amino acid residues. In other words, the smaller the average distance between the hydrophobic amino acid residues at the binding sites between the two and the more the number of them, and the stronger the oestrogen activity expression degree of PCBS derivative molecules. Therefore, hydrophobic interactions between PCB derivatives and the oestrogen receptor can be reduced by altering the microenvironmental conditions in humans. This reduces the ability of PCB derivatives to bind to the oestrogen receptor and can effectively modulate the risk of residual PCB derivatives to produce oestrogenic activity in humans.

scholarly journals Metabolome and proteome analyses reveal transcriptional misregulation in glycolysis of engineered E. coli

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chun-Ying Wang ◽  
Martin Lempp ◽  
Niklas Farke ◽  
Stefano Donati ◽  
Timo Glatter ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Binding Site ◽  
Metabolic Pathways ◽  
Glycerol Production ◽  
Inducible Promoters ◽  
E Coli ◽  
Inhibition Of Glycolysis ◽  
Underlying Mechanisms ◽  
Rate Limiting ◽  
Engineered Bacteria

AbstractSynthetic metabolic pathways are a burden for engineered bacteria, but the underlying mechanisms often remain elusive. Here we show that the misregulated activity of the transcription factor Cra is responsible for the growth burden of glycerol overproducing E. coli. Glycerol production decreases the concentration of fructose-1,6-bisphoshate (FBP), which then activates Cra resulting in the downregulation of glycolytic enzymes and upregulation of gluconeogenesis enzymes. Because cells grow on glucose, the improper activation of gluconeogenesis and the concomitant inhibition of glycolysis likely impairs growth at higher induction of the glycerol pathway. We solve this misregulation by engineering a Cra-binding site in the promoter controlling the expression of the rate limiting enzyme of the glycerol pathway to maintain FBP levels sufficiently high. We show the broad applicability of this approach by engineering Cra-dependent regulation into a set of constitutive and inducible promoters, and use one of them to overproduce carotenoids in E. coli.

Sequence analysis, structure prediction of receptor proteins and In silico study of potential inhibitors for management of life threatening COVID-19

2021 ◽  
Vol 18 ◽  
Author(s):  
Hriday K. Basak ◽  
Soumen Saha ◽  
Joydeep Ghosh ◽  
Uttam Paswan ◽  
Sujoy Karmakar ◽  
...  
Keyword(s):  
Binding Site ◽  
Ursolic Acid ◽  
Density Functional ◽  
Actinomycin D ◽  
3D Structure ◽  
Natural Compounds ◽  
Surface Glycoprotein ◽  
Basis Set ◽  
3D Structures ◽  
Potential Inhibitors

Background: Treatment of the Covid-19 pandemic caused by the highly contagious and pathogenic SARS-CoV-2 is a global menace. Day by day this pandemic is getting worse. Doctors, Scientists and Researchers across the world are urgently scrambling for a cure for novel corona virus and continuously working at break neck speed to develop vaccine or drugs. But to date, there are no specific drugs or vaccine available in the market to cope up the virus. Objective: The present study helps us to elucidate 3D structures of SARS-CoV-2 proteins and also to identify best natural compounds as potential inhibitors against COVID-19. Methods: The 3D structures of the proteins were constructed using Modeller 9.16 modeling tool. Modelled proteins were validated with PROCHECK by Ramachandran plot analysis. In this study a small library of natural compounds (fifty compounds) was docked to the ACE2 binding site of the modelled surface glycoprotein of SARS-CoV-2 using Auto Dock Vina to repurpose these inhibitors for SARS-CoV-2. Conceptual density functional theory calculations of best eight compounds had been performed by Gaussian-09. Geometry optimizations for these molecules were done at M06-2X/ def2-TZVP level of theory. ADME parameters, pharmacokinetic properties and drug likeliness of the compounds were analyzed in the swissADME website. Results: In this study we analysed the sequences of surface glycoprotein, nucleocapsid phosphoprotein and envelope protein obtained from different parts of the globe. We have modelled all the different sequences of surface glycoprotein and envelop protein in order to derive 3D structure of a molecular target which is essential for the development of therapeutics. Different electronic properties of the inhibitors have been calculated using DFT through M06-2X functional with def2-TZVP basis set. Docking result at the hACE2 binding site of all modelled surface glycoproteins of SARS-CoV-2 showed that all the eight inhibitors (Actinomycin D, avellanin C, ichangin, kanglemycin A, obacunone, ursolic acid, ansamiotocin P-3 and isomitomycin A) studied here many folds better compared to hydroxychloroquine which has been found to be effective to treat patients suffering fromCOVID-19 pandemic. All the inhibitors meet most of criteria of drug likeness assessment. Conclusion: We will expect that eight compounds (Actinomycin D, avellanin C, ichangin, kanglemycin A, obacunone, ursolic acid, ansamiotocin P-3 and isomitomycin A) can be used as potential inhibitors against SARS-CoV-2.

Anti-aging natural compounds and their role in the regulation of metabolic pathways leading to longevity

2021 ◽  
Vol 21 ◽  
Author(s):  
Aqsa Muzammil ◽  
Muhammad Waqas ◽  
Ahitsham Umar ◽  
Muhammad Sufyan ◽  
Abdur Rehman ◽  
...  
Keyword(s):  
Natural Products ◽  
Metabolic Pathways ◽  
Natural Compounds ◽  
Chronic Obstructive ◽  
Telomere Shortening ◽  
Age Related ◽  
Chronic Obstructive Pulmonary Diseases ◽  
Extended Lifespan ◽  
Ancient Times

: Aging is an unavoidable process, leads to cell senescence due to physiochemical changes in an organism. Anti-aging remedies have always been of great interest since ancient times. The purpose of anti-aging activities is to increase the life span and the quality of life. Anti-aging activities are primarily involved in the therapies of age-related disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), cardiovascular diseases, cancer and chronic obstructive pulmonary diseases. These diseases are triggered by multiple factors that are involved in numerous molecular pathways including telomere shortening, NF-κB pathway, adiponectin receptor pathway, insulin and IGF signaling pathway, AMPK, mTOR and mitochondria dysfunction. Natural products are known as effective molecules to delay the aging process through influencing metabolic pathways and thus ensure an extended lifespan. These natural compounds are being utilized in drug design and development through computational and high throughput techniques for effective pro-longevity drugs. A comprehensive study of natural compounds demonstrated with their anti-aging activities along with databases of natural products for drug designing was executed and summarized in this review article.

scholarly journals Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

2012 ◽  
Vol 8 ◽  
pp. 1858-1866 ◽  
Author(s):  
Julia Meier ◽  
Kristin Kassler ◽  
Heinrich Sticht ◽  
Jutta Eichler
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Envelope Glycoprotein ◽  
Conformational Stability ◽  
Cellular Receptor ◽  
Binding Assays ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Hiv 1

Based on the structure of the HIV-1 glycoprotein gp120 in complex with its cellular receptor CD4, we have designed and synthesized peptides that mimic the binding site of CD4 for gp120. The ability of these peptides to bind to gp120 can be strongly enhanced by increasing their conformational stability through cyclization, as evidenced by binding assays, as well as through molecular-dynamics simulations of peptide–gp120 complexes. The specificity of the peptide–gp120 interaction was demonstrated by using peptide variants, in which key residues for the interaction with gp120 were replaced by alanine or D-amino acids.

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