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Displaying publications 81 - 100 of 626 in total

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Steroids from Diplazium esculentum: Antiplasmodial activity and molecular docking studies to investigate their binding modes

Safar HF, Ali AH, Zakaria NH, Kamal N, Hassan NI, Agustar HK, et al.

Trop Biomed, 2022 Dec 01;39(4):552-558.
PMID: 36602215 DOI: 10.47665/tb.39.4.011

Diplazium esculentum is an edible fern commonly consumed by the local community in Malaysia either as food or medicine. Isolation work on the ethyl acetate extract of the stem of D. esculentum resulted in the purification of two steroids, subsequently identified as stigmasterol (compound 1) and ergosterol5,8-endoperoxide (compound 2). Upon further testing, compound 2 displayed strong inhibitory activity against the Plasmodium falciparum 3D7 (chloroquine-sensitive) strain, with an IC50 of 4.27±1.15 µM, while compound 1 was inactive. In silico data revealed that compound 2 showed good binding affinity to P. falciparum-Sarco endoplasmic reticulum calcium-dependent ATPase (PfATP6); however, compound 1 did not show an antiplasmodial effect due to the lack of a peroxide moiety in the chemical structure. Our data suggested that the antiplasmodial activity of compound 2 from D. esculentum might be due to the inhibition of PfATP6, which resulted in both in vitro and in silico inhibitory properties.

Matched MeSH terms: Molecular Docking Simulation
Pan-genome analysis and molecular docking unveil the biocontrol potential of Bacillus velezensis VB7 against Phytophthora infestans

Kadiri M, Sevugapperumal N, Nallusamy S, Ragunathan J, Ganesan MV, Alfarraj S, et al.

Microbiol Res, 2023 Mar;268:127277.
PMID: 36577205 DOI: 10.1016/j.micres.2022.127277

Management of late blight of potato incited by Phytophthora infestans remains a major challenge. Coevolution of pathogen with resistant strains and the rise of fungicide resistance have made it more challenging to prevent the spread of P. infestans. Here, the anti-oomycete potential of Bacillus velezensis VB7 against P. infestans through pan-genome analysis and molecular docking were explored. The Biocontrol potential of VB7 against P. infestans was assessed using a confrontational assay. The biomolecules from the inhibition zone were identified and subjected to in silico analysis against P. infestans target proteins. Nucleotide sequences for 54 B. velezensis strains from different geographical locations were used for pan-genome analysis. The confrontational assay revealed the anti-oomycetes potential of VB7 against P. infestans. Molecular docking confirmed that the penicillamine disulfide had the maximum binding energy with eight effector proteins of P. infestans. Besides, scanning electron microscopic observations of P. infestans interaction with VB7 revealed structural changes in hypha and sporangia. Pan-genome analysis between 54 strains of B. velezensis confirmed that the core genome had 2226 genes, and it has an open pan-genome. The present study confirmed the anti-oomycete potential of B. velezensis VB7 against P. infestans and paved the way to explore the genetic potential of VB7.

Matched MeSH terms: Molecular Docking Simulation
In silico analysis of a putative dehalogenase from the genome of halophilic bacterium Halomonas smyrnensis AAD6T

Oyewusi HA, Akinyede KA, Abdul Wahab R, Huyop F

J Biomol Struct Dyn, 2023 Jan;41(1):319-335.
PMID: 34854349 DOI: 10.1080/07391102.2021.2006085

Microbial-assisted removal of natural or synthetic pollutants is the prevailing green, low-cost technology to treat polluted environments. However, the challenge with enzyme-assisted bioremediation is the laborious nature of dehalogenase-producing microorganisms' bioprospecting. This bottleneck could be circumvented by in-silico analysis of certain microorganisms' whole-genome sequences to predict their protein functions and enzyme versatility for improved biotechnological applications. Herein, this study performed structural analysis on a dehalogenase (DehHsAAD6) from the genome of Halomonas smyrnensis AAD6 by molecular docking and molecular dynamic (MD) simulations. Other bioinformatics tools were also employed to identify substrate preference (haloacids and haloacetates) of the DehHsAAD6. The DehHsAAD6 preferentially degraded haloacids and haloacetates (-3.2-4.8 kcal/mol) and which formed three hydrogen bonds with Tyr12, Lys46, and Asp182. MD simulations data revealed the higher stability of DehHsAAD6-haloacid- (RMSD 0.22-0.3 nm) and DehHsAAD6-haloacetates (RMSF 0.05-0.14 nm) complexes, with the DehHsAAD6-L-2CP complex being the most stable. The detail of molecular docking calculations ranked complexes with the lowest binding free energies as: DehHsAAD6-L-2CP complex (-4.8 kcal/mol) = DehHsAAD6-MCA (-4.8 kcal/mol) < DehHsAAD6-TCA (-4.5 kcal/mol) < DehHsAAD6-2,3-DCP (-4.1 kcal/mol) < DehHsAAD6-D-2CP (-3.9 kcal/mol) < DehHsAAD6-2,2-DCP (-3.5 kcal/mol) < DehHsAAD6-3CP (-3.2 kcal/mol). In a nutshell, the study findings offer valuable perceptions into the elucidation of possible reaction mechanisms of dehalogenases for extended substrate specificity and higher catalytic activity.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
Ensemble-based, high-throughput virtual screening of potential inhibitor targeting putative farnesol dehydrogenase of Metisa plana (Lepidoptera: Psychidae)

Zifruddin AN, Mohamad Yusoff MA, Abd Ghani NS, Nor Muhammad NA, Lam KW, Hassan M

Comput Biol Chem, 2023 Apr;103:107811.
PMID: 36645937 DOI: 10.1016/j.compbiolchem.2023.107811

Metisa plana (Lepidoptera: Psychidae) bagworm is a leaf-eater caterpillar ubiquitously found as a damaging pest in oil palm plantations, specifically in Malaysia. Various strategies have been implemented, including the usage of chemical insecticides. However, the main challenges include the development of insecticide resistance and its detrimental effects on the environment and non-target organisms. Therefore, a biorational insecticide is introduced by targeting the juvenile hormone (JH) biosynthetic pathway, which is mainly present in the insect and vital for the insect's growth, diapause, metamorphosis, and adult reproduction. This study aimed to investigate the potential inhibitor for the rate-limiting enzyme involved in the JH pathway known as farnesol dehydrogenase. A 255 amino acids sequence encoded for the putative M. plana farnesol dehydrogenase (MpFolDH) open reading frame had been identified and isolated. The three-dimensional structure of MpFolDH was predicted to have seven β- sheets with α-helices at both sides, showing typical characteristics for classical short-chain dehydrogenase and associated with oxidoreductase activity. Then, the ensemble-based virtual screening was conducted based on the ZINC20 database, in which 43 768 compounds that fulfilled pesticide-likeness criteria were screened by site-specific molecular docking. After a short molecular dynamics simulation (5 ns) was conducted towards 102 compounds, only the top 10 compounds based on their most favourable binding energy were selected for a more extended simulation (100 ns). Based on the protein-ligand stability, protein compactness, residues rigidity, binding interaction, binding energy throughout the 100 ns simulation, and physicochemical analysis, ZINC000408743205 was selected as a potential inhibitor for this enzyme. Amino acids decomposition analysis indicates Ile18, Ala95, Val198 and Val202 were the critical contributor residues for MpFolDH-inhibitors(s) complex.

Matched MeSH terms: Molecular Docking Simulation
Multi-Targeted Molecular Docking and Drug-Likeness Evaluation of some Nitrogen Heterocyclic Compounds Targeting Proteins Involved in the Development of COVID-19

Hui LY, Mun CS, Sing LC, Rajak H, Karunakaran R, Ravichandran V

Med Chem, 2023;19(3):297-309.
PMID: 35713125 DOI: 10.2174/1573406418666220616110351

BACKGROUND: The severe acute respiratory syndrome coronavirus-2 is causing a disaster through coronavirus disease-19 (COVID-19), affecting the world population with a high mortality rate. Although numerous scientific efforts have been made, we do not have any specific drug for COVID-19 treatment.
OBJECTIVE: Aim of the present study was to analyse the molecular interaction of nitrogen heterocyclic based drugs (hydroxychloroquine, remdesivir and lomefloxacin) with various SARSCoV- 2 proteins (RdRp, PLPro, Mpro and spike proteins) using a molecular docking approach.
METHODS: We have performed docking study using PyRx software, and Discovery Studio Visualizer was used to visualise the molecular interactions. The designed nitrogen heterocyclic analogues were checked for Lipinski's rule of five, Veber's Law and Adsorption, Distribution, Metabolism, and Excretion (ADME) threshold. After obtaining the docking results of existing nitrogen heterocyclic drugs, we modified the selected drugs to get molecules with better affinity against SARS-CoV-2.
RESULTS: Hydroxychloroquine bound to RdRp, spike protein, PLPro and Mpro at -5.2, -5.1, -6.7 and -6.0 kcal/mol, while remdesivir bound to RdRp, spike protein, PLPro, and Mpro at -6.1, -6.9, -6.4 and -6.9 kcal/mol, respectively. Lomefloxacin bound to RdRp, spike protein, PLPro and Pro at -6.4, -6.6, -7.2 and -6.9 kcal/mol. ADME studies of all these compounds indicated lipophilicity and high gastro intestine absorbability. The modified drug structures possess better binding efficacy towards at least one target than their parent compounds.
CONCLUSION: The outcome reveals that the designed nitrogen heterocyclics could contribute to developing the potent inhibitory drug SARS-CoV-2 with strong multi-targeted inhibition ability and reactivity.

Matched MeSH terms: Molecular Docking Simulation
Synthesis of new urease enzyme inhibitors as antiulcer drug and computational study

Taha M, Ismail S, Imran S, Almandil NB, Alomari M, Rahim F, et al.

J Biomol Struct Dyn, 2022 Nov;40(18):8232-8247.
PMID: 33860726 DOI: 10.1080/07391102.2021.1910072

In search of potent urease inhibitor indole analogues (1-22) were synthesized and evaluated for their urease inhibitory potential. All analogues (1-22) showed a variable degree of inhibitory interaction potential having IC50 value ranging between 0.60 ± 0.05 to 30.90 ± 0.90 µM when compared with standard thiourea having IC50 value 21.86 ± 0.90 µM. Among the synthesized analogues, the compounds 1, 2, 3, 5, 6, 8, 12, 14, 18, 20 and 22 having IC50 value 3.10 ± 0.10, 1.20 ± 0.10, 4.60 ± 0.10, 0.60 ± 0.05, 5.30 ± 0.20, 2.50 ± 0.10, 7.50 ± 0.20, 3.90 ± 0.10, 3.90 ± 0.10, 2.30 ± 0.05 and 0.90 ± 0.05 µM respectively were found many fold better than the standard thiourea. All other analogues showed better urease interaction inhibition. Structure activity relationship (SAR) has been established for all analogues containing different substituents on the phenyl ring. To understand the binding interaction of most active analogues with enzyme active site docking study were performed.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
Therapeutically important bioactive compounds of the genus Polygonum L. and their possible interventions in clinical medicine

Cherian S, Hacisayidli KM, Kurian R, Mathews A

J Pharm Pharmacol, 2023 Mar 12;75(3):301-327.
PMID: 36757388 DOI: 10.1093/jpp/rgac105

OBJECTIVES: Increasing literature data have suggested that the genus Polygonum L. possesses pharmacologically important plant secondary metabolites. These bioactive compounds are implicated as effective agents in preclinical and clinical practice due to their pharmacological effects such as anti-inflammatory, anticancer, antidiabetic, antiaging, neuroprotective or immunomodulatory properties among many others. However, elaborate pharmacological and clinical data concerning the bioavailability, tissue distribution pattern, dosage and pharmacokinetic profiles of these compounds are still scanty.
KEY FINDINGS: The major bioactive compounds implicated in the therapeutic effects of Polygonum genus include phenolic and flavonoid compounds, anthraquinones and stilbenes, such as quercetin, resveratrol, polydatin and others, and could serve as potential drug leads or as adjuvant agents. Data from in-silico network pharmacology and computational molecular docking studies are also highly helpful in identifying the possible drug target of pathogens or host cell machinery.
SUMMARY: We provide an up-to-date overview of the data from pharmacodynamic, pharmacokinetic profiles and preclinical (in-vitro and in-vivo) investigations and the available clinical data on some of the therapeutically important compounds of genus Polygonum L. and their medical interventions, including combating the outbreak of the COVID-19 pandemic.

Matched MeSH terms: Molecular Docking Simulation
In silico analysis prediction of HepTH1-5 as a potential therapeutic agent by targeting tumour suppressor protein networks

Azemin WA, Alias N, Ali AM, Shamsir MS

J Biomol Struct Dyn, 2023 Mar;41(4):1141-1167.
PMID: 34935583 DOI: 10.1080/07391102.2021.2017349

Many studies reported that the activation of tumour suppressor protein, p53 induced the human hepcidin expression. However, its expression decreased when p53 was silenced in human hepatoma cells. Contrary to Tilapia hepcidin TH1-5, HepTH1-5 was previously reported to trigger the p53 activation through the molecular docking approach. The INhibitor of Growth (ING) family members are also shown to directly interact with p53 and promote cell cycle arrest, senescence, apoptosis and participate in DNA replication and DNA damage responses to suppress the tumour initiation and progression. However, the interrelation between INGs and HepTH1-5 remains unknown. Therefore, this study aims to identify the mechanism and their protein interactions using in silico approaches. The finding revealed that HepTH1-5 and its ligands had interacted mostly on hotspot residues of ING proteins which involved in histone modifications via acetylation, phosphorylation, and methylation. This proves that HepTH1-5 might implicate in an apoptosis signalling pathway and preserve the protein structure and function of INGs by reducing the perturbation of histone binding upon oxidative stress response. This study would provide theoretical guidance for the design and experimental studies to decipher the role of HepTH1-5 as a potential therapeutic agent for cancer therapy. Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
Synthesis, in vitro biological screening and docking study of benzo[d]oxazole bis Schiff base derivatives as a potent anti-Alzheimer agent

Taha M, Rahim F, Zaman K, Anouar EH, Uddin N, Nawaz F, et al.

J Biomol Struct Dyn, 2023 Mar;41(5):1649-1664.
PMID: 34989316 DOI: 10.1080/07391102.2021.2023640

We have synthesized benzo[d]oxazole derivatives (1-21) through a multistep reaction. Alteration in the structure of derivatives was brought in the last step via using various substituted aromatic aldehydes. In search of an anti-Alzheimer agent, all derivatives were evaluated against acetylcholinesterase and butyrylcholinesterase enzyme under positive control of standard drug donepezil (IC50 = 0.016 ± 0.12 and 4.5 ± 0.11 µM) respectively. In case of acetylcholinesterase enzyme inhibition, derivatives 8, 9 and 18 (IC50 = 0.50 ± 0.01, 0.90 ± 0.05 and 0.3 ± 0.05 µM) showed very promising inhibitory potentials. While in case of butyrylcholinesterase enzyme inhibition, most of the derivatives like 6, 8, 9, 13, 15, 18 and 19 (IC50 = 2.70 ± 0.10, 2.60 ± 0.10, 2.20 ± 0.10, 4.25 ± 0.10, 3.30 ± 0.10, 0.96 ± 0.05 and 3.20 ± 0.10 µM) displayed better inhibitory potential than donepezil. Moreover, derivative 18 is the most potent one among the series in both inhibitions. The binding interaction of derivatives with the active gorge of the enzyme was confirmed via a docking study. Furthermore, the binding interaction between derivatives and the active site of enzymes was correlated through the SAR study. Structures of all derivatives were confirmed through spectroscopic techniques such as 1H-NMR, 13C-NMR and HREI-MS, respectively.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
Molecular modelling and structure-activity relationship of a natural derivative of o-hydroxybenzoate as a potent inhibitor of dual NSP3 and NSP12 of SARS-CoV-2: in silico study

Ayipo YO, Ahmad I, Najib YS, Sheu SK, Patel H, Mordi MN

J Biomol Struct Dyn, 2023 Mar;41(5):1959-1977.
PMID: 35037841 DOI: 10.1080/07391102.2022.2026818

The nsp3 macrodomain and nsp12 (RdRp) enzymes are strongly implicated in the virulent regulation of the host immune response and viral replication of SARS-CoV-2, making them plausible therapeutic targets for mitigating infectivity. Remdesivir remains the only FDA-approved small-molecule inhibitor of the nsp12 in clinical conditions while none has been approved yet for the nsp3 macrodomain. In this study, 69,067 natural compounds from the IBScreen database were screened for efficacious potentials with mechanistic multitarget-directed inhibitory pharmacology against the dual targets using in silico approaches. Standard and extra precision (SP and XP) Maestro glide docking analyses were employed to evaluate their inhibitory interactions against the enzymes. Four compounds, STOCK1N-45901, 03804, 83408, 08377 consistently showed high XP scores against the respective targets and interacted strongly with pharmacologically essential amino acid and RNA residues, in better terms than the standard, co-crystallized inhibitors, GS-441524 and remdesivir. Further assessments through the predictions of ADMET and mutagenicity distinguished STOCK1N-45901, a natural derivative of o-hydroxybenzoate as the most promising candidate. The ligand maintained a good conformational and thermodynamic stability in complex with the enzymes throughout the trajectories of 100 ns molecular dynamics, indicated by RMSD, RMSF and radius of gyration plots. Its binding free energy, MM-GBSA was recorded as -54.24 and -31.77 kcal/mol against the respective enzyme, while its structure-activity relationships confer high probabilities as active antiviral, anti-inflammatory, antiinfection, antitussive and peroxidase inhibitor. The IBScreen database natural product, STOCK1N-45901 (2,3,4,5,6-pentahydroxyhexyl o-hydroxybenzoate) is thus recommended as a potent inhibitor of dual nsp3 and nsp12 of SARS-CoV-2 for further study. Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
Use of computational and wet lab techniques to examine the molecular association between a potent hepatitis C virus inhibitor, PSI-6206 and human serum albumin

Abubakar M, Mohamed SB, Abd Halim AA, Tayyab S

Spectrochim Acta A Mol Biomol Spectrosc, 2023 Jun 05;294:122543.
PMID: 36868020 DOI: 10.1016/j.saa.2023.122543

This study explores the plausible molecular interaction between a potent hepatitis C virus inhibitor, PSI-6206 (PSI), and human serum albumin (HSA), a primary transporter in blood plasma. Results obtained from both computational viz. molecular docking and molecular dynamics (MD) simulation and wet lab techniques such as UV absorption, fluorescence, circular dichroism (CD), and atomic force microscopy (AFM) complemented each other. While docking results identified PSI binding to subdomain IIA (Site I) of HSA by forming six hydrogen bonds, MD simulations signified the complex stability throughout the 50,000 ps. A consistent cutback in the Stern-Volmer quenching constant (Ksv) along with rising temperatures supported the static mode of fluorescence quenching in response to PSI addition and implied the development of the PSI-HSA complex. This discovery was backed by the alteration of the HSA UV absorption spectrum, a larger value (>1010 M-1.s-1) of the bimolecular quenching rate constant (kq) and the AFM-guided swelling of the HSA molecule, in the presence of PSI. Moreover, the fluorescence titration results revealed a modest binding affinity (4.27-6.25×103 M-1) in the PSI-HSA system, involving hydrogen bonds, van der Waals and hydrophobic interactions, as inferred from ΔS = + 22.77 J mol-1 K-1 and ΔH = - 11.02 KJ mol-1values. CD and 3D fluorescence spectra reminded significant adjustment in the 2° and 3° structures and modification in the Tyr/Trp microenvironment of the protein in the PSI-bound state. The results obtained from drug competing experiments also advocated the binding location of PSI in HSA as Site I.

Matched MeSH terms: Molecular Docking Simulation
Targeting Acanthamoeba proteins interaction with flavonoids of Propolis extract by in vitro and in silico studies for promising therapeutic effects

Sama-Ae I, Sangkanu S, Siyadatpanah A, Norouzi R, Chuprom J, Mitsuwan W, et al.

F1000Res, 2022;11:1274.
PMID: 36936052 DOI: 10.12688/f1000research.126227.1

Background : Propolis is a natural resinous mixture produced by bees. It provides beneficial effects on human health in the treatment/management of many diseases. The present study was performed to demonstrate the anti- Acanthamoeba activity of ethanolic extracts of Propolis samples from Iran. The interactions of the compounds and essential proteins of Acanthamoeba were also visualized through docking simulation. Methods: The minimal inhibitory concentrations (MICs) of Propolis extract against Acanthamoeba trophozoites and cysts was determined in vitro. In addition, two-fold dilutions of each of the agents were tested for encystment, excystment and adhesion inhibitions. Three major compounds of Propolis extract such as chrysin, tectochrysin and pinocembrin have been selected in molecular docking approach to predict the compounds that might be responsible for encystment, excystment and adhesion inhibitions of A. castellanii. Furthermore, to confirm the docking results, molecular dynamics (MD) simulations were also carried out for the most promising two ligand-pocket complexes from docking studies. Results : The minimal inhibitory concentrations (MICs) 62.5 and 125 µg/mL of the most active Propolis extract were assessed in trophozoites stage of Acanthamoeba castellanii ATCC30010 and ATCC50739, respectively. At concentrations lower than their MICs values (1/16 MIC), Propolis extract revealed inhibition of encystation. However, at 1/2 MIC, it showed a potential inhibition of excystation and anti-adhesion. The molecular docking and dynamic simulation revealed the potential capability of Pinocembrin to form hydrogen bonds with A. castellanii Sir2 family protein (AcSir2), an encystation protein of high relevance for this process in Acanthamoeba. Conclusions : The results obtained provided a candidate for the development of therapeutic drugs against Acanthamoeba infection. In vivo experiments and clinical trials are necessary to support this claim.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Mpropred: A machine learning (ML) driven Web-App for bioactivity prediction of SARS-CoV-2 main protease (Mpro) antagonists

Ferdous N, Reza MN, Hossain MU, Mahmud S, Napis S, Chowdhury K, et al.

PLoS One, 2023;18(6):e0287179.
PMID: 37352252 DOI: 10.1371/journal.pone.0287179

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged in 2019 and still requiring treatments with fast clinical translatability. Frequent occurrence of mutations in spike glycoprotein of SARS-CoV-2 led the consideration of an alternative therapeutic target to combat the ongoing pandemic. The main protease (Mpro) is such an attractive drug target due to its importance in maturating several polyproteins during the replication process. In the present study, we used a classification structure-activity relationship (CSAR) model to find substructures that leads to to anti-Mpro activities among 758 non-redundant compounds. A set of 12 fingerprints were used to describe Mpro inhibitors, and the random forest approach was used to build prediction models from 100 distinct data splits. The data set's modelability (MODI index) was found to be robust, with a value of 0.79 above the 0.65 threshold. The accuracy (89%), sensitivity (89%), specificity (73%), and Matthews correlation coefficient (79%) used to calculate the prediction performance, was also found to be statistically robust. An extensive analysis of the top significant descriptors unveiled the significance of methyl side chains, aromatic ring and halogen groups for Mpro inhibition. Finally, the predictive model is made publicly accessible as a web-app named Mpropred in order to allow users to predict the bioactivity of compounds against SARS-CoV-2 Mpro. Later, CMNPD, a marine compound database was screened by our app to predict bioactivity of all the compounds and results revealed significant correlation with their binding affinity to Mpro. Molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) analysis showed improved properties of the complexes. Thus, the knowledge and web-app shown herein can be used to develop more effective and specific inhibitors against the SARS-CoV-2 Mpro. The web-app can be accessed from https://share.streamlit.io/nadimfrds/mpropred/Mpropred_app.py.

Matched MeSH terms: Molecular Docking Simulation
Fulltext In Silico Drug Design of Anti-Breast Cancer Agents

Rajagopal K, Kalusalingam A, Bharathidasan AR, Sivaprakash A, Shanmugam K, Sundaramoorthy M, et al.

Molecules, 2023 May 18;28(10).
PMID: 37241915 DOI: 10.3390/molecules28104175

Cancer is a condition marked by abnormal cell proliferation that has the potential to invade or indicate other health issues. Human beings are affected by more than 100 different types of cancer. Some cancer promotes rapid cell proliferation, whereas others cause cells to divide and develop more slowly. Some cancers, such as leukemia, produce visible tumors, while others, such as breast cancer, do not. In this work, in silico investigations were carried out to investigate the binding mechanisms of four major analogs, which are marine sesquiterpene, sesquiterpene lactone, heteroaromatic chalcones, and benzothiophene against the target estrogen receptor-α for targeting breast cancer using Schrödinger suite 2021-4. The Glide module handled the molecular docking experiments, the QikProp module handled the ADMET screening, and the Prime MM-GB/SA module determined the binding energy of the ligands. The benzothiophene analog BT_ER_15f (G-score -15.922 Kcal/mol) showed the best binding activity against the target protein estrogen receptor-α when compared with the standard drug tamoxifen which has a docking score of -13.560 Kcal/mol. TRP383 (tryptophan) has the highest interaction time with the ligand, and hence it could act for a long time. Based on in silico investigations, the benzothiophene analog BT_ER_15f significantly binds with the active site of the target protein estrogen receptor-α. Similar to the outcomes of molecular docking, the target and ligand complex interaction motif established a high affinity of lead candidates in a dynamic system. This study shows that estrogen receptor-α targets inhibitors with better potential and low toxicity when compared to the existing market drugs, which can be made from a benzothiophene derivative. It may result in considerable activity and be applied to more research on breast cancer.

Matched MeSH terms: Molecular Docking Simulation
Rational design of mini protein mimicking uricase: Encapsulation in ZIF-8 for uric acid detection

Abdul Aziz SFN, Rahim ASMA, Normi YM, Alang Ahmad SA, Salleh AB

Proteins, 2023 Jul;91(7):967-979.
PMID: 36908223 DOI: 10.1002/prot.26485

Five mini proteins mimicking uricase comprising 20, 40, 60, 80, and 100 amino acids were designed based on the conserved active site residues within the same dimer, using the crystal structure of tetrameric uricase from Arthrobacter globiformis (PDB ID: 2yzb) as a template. Based on molecular docking analysis, the smallest mini protein, mp20, shared similar residues to that of native uricase that formed hydrogen bonds with uric acid and was chosen for further studies. Although purified recombinant mp20 did not exhibit uricase activity, it showed specific binding towards uric acid and evinced excellent thermotolerance and structural stability at temperatures ranging from 10°C to 100°C, emulating its natural origin. To explore the potential of mp20 as a bioreceptor in uric acid sensing, mp20 was encapsulated within zeolitic imidazolate framework-8 (mp20@ZIF-8) followed by the modification on rGO-screen printed electrode (rGO/SPCE) to maintain the structural stability. An irreversible anodic peak and increased semicircular arcs of the Nyquist plot with an increase of the analyte concentrations were observed by utilizing cyclic voltammetry and electrochemical impedance spectroscopy (EIS), suggesting the detection of uric acid occurred, which is based on substrate-mp20 interaction.

Matched MeSH terms: Molecular Docking Simulation
Fulltext In Silico and In Vitro Methods in the Characterization of Beta-Carotene as Pharmaceutical Material via Acetylcholine Esterase Inhibitory Actions

Muthuraman A, Ramesh M, Mustaffa F, Nadeem A, Nishat S, Paramakrishnan N, et al.

Molecules, 2023 May 26;28(11).
PMID: 37298835 DOI: 10.3390/molecules28114358

Molecular docking is widely used in the assessment of the therapeutic potential of pharmaceutical agents. The binding properties of beta-carotene (BC) to acetylcholine esterase (AChE) proteins were characterized using the molecular docking method. The mechanism of AChE inhibition was assessed by an experimental in vitro kinetic study. In addition, the role of BC action was tested by the zebrafish embryo toxicity test (ZFET). The results of the docking ability of BC to AChE showed significant ligand binding mode. The kinetic parameter, i.e., the low AICc value shown as the compound was the competitive type of inhibition of AChE. Further, BC also showed mild toxicity at a higher dose (2200 mg/L) in ZFET assessment with changes in biomarkers. The LC50 value of BC is 1811.94 mg/L. Acetylcholine esterase (AChE) plays a pivotal role in the hydrolysis of acetylcholine, which leads to the development of cognitive dysfunction. BC possesses the regulation of acetylcholine esterase (AChE) and acid phosphatase (AP) activity to prevent neurovascular dysfunction. Therefore, the characterization of BC could be used as a pharmaceutical agent for the treatment of cholinergic neurotoxicity-associated neurovascular disorders such as developmental toxicity, vascular dementia, and Alzheimer's disease due to its AChE and AP inhibitory actions.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Design, Synthesis, and in-vitro Protease Inhibition Assay of Linear Pentapeptides as Potential Dengue Virus NS2B/NS3 Protease Inhibitors

Abdalsatar Abdalrazaq N, Ezleen Binti Kamarulzaman E

Arch Razi Inst, 2022 Apr;77(2):843-852.
PMID: 36284983 DOI: 10.22092/ARI.2022.357124.1980

Nowadays dengue virus infection (DENV) is one of the major health complications in the world. Although DENV is an old and common disease, unfortunately, until now, there are no specific relevant treatments available for it. This study, therefore, aimed to design, as well as synthesize selective peptide inhibitors, and investigate their activity by in-vitro NS2B/NS3 protease inhibition assay. The design of the peptide ligands was based on studying the interactions with the dengue NS2B/NS3 protease using the computational docking technique in the MOE and AutoDock (version 4.2) software. To this end, the researchers designed 26 linear pentapeptides based on previous studies. It was revealed that two linear pentapeptides (i.e., GKRRK and KRRRK) are the best potential inhibitors. Furthermore, based on the findings of the two independent docking programs, the peptide GKRRK was synthesized by solid-phase peptide synthesis and its structure was confirmed. The in-vitro protease inhibitor study was conducted for these two peptides to examine their activity against the dengue virus using a protin in as a control. It was found that the designed potential peptides possess interesting inhibition against the NS2B/NS3 protease. Additionally, the findings showed that the peptide GKRRK had the highest percentage of inhibition (71.11%) at 100 µM with the IC50 of 48.87 µM; therefore, this linear peptide could serve as a good inhibitor for the DENV.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Catalytic response and molecular simulation studies in the development of synthetic routes in trimeric triaryl pyridinium type ionic liquids

Tamilarasan R, Subramani A, Sasikumar G, Ganapathi P, Karthikeyan S, Ponnusamy S, et al.

Sci Rep, 2023 Mar 17;13(1):4453.
PMID: 36932171 DOI: 10.1038/s41598-023-31476-0

Under conventional and silica-supported Muffle furnace methods, water-soluble substituted trimeric triaryl pyridinium cations with various inorganic counter anions are synthesized. The solvent-free synthesis method is superior to the conventional method in terms of non-toxicity, quicker reaction times, ease of workup, and higher yields. Trimeric substituted pyridinium salts acted as excellent catalytic responses for the preparation of Gem-bisamide derivatives compared with available literature. To evaluate the molecular docking, benzyl/4-nitrobenzyl substituted triaryl pyridinium salt compounds with VEGFR-2 kinase were used with H-bonds, π-π stacking, salt bridges, and hydrophobic contacts. The results showed that the VEGFR-2 kinase protein had the most potent inhibitory activity. Intriguingly, the compound [NBTAPy]PF6- had a strongly binds to VEGFR-2 kinase and controlled its activity in cancer treatment and prevention.

Matched MeSH terms: Molecular Docking Simulation
In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

Mohamed EAR, Abdel-Rahman IM, Zaki MEA, Al-Khdhairawi A, Abdelhamid MM, Alqaisi AM, et al.

J Mol Model, 2023 Feb 20;29(3):70.
PMID: 36808314 DOI: 10.1007/s00894-023-05457-z

BACKGROUND: In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.
METHODS: As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.
RESULTS: The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

Matched MeSH terms: Molecular Docking Simulation
Synergistic effect of hydrophilic polyglycerol fatty acid esters and protein on the stability of interfacial membrane in low-fat aerated emulsions with different homogenization conditions

Han W, Chai X, Zaaboul F, Sun Y, Tan CP, Liu Y

Food Chem, 2024 Mar 01;435:137584.
PMID: 37774617 DOI: 10.1016/j.foodchem.2023.137584

This study investigates the impact of various chain lengths of hydrophilic polyglycerol fatty acid esters (HPGEs), namely SWA-10D, M-7D and M-10D on protein interactions and their influence on the surface morphology and interfacial properties of low-fat aerated emulsions under different pressures conditions. M-7D and M-10D samples exhibited larger particle sizes, higher ζ-potential and rougher surface compared to SWA-10D sample at 1 % concentration of HPGEs. Consequently, M-7D and M-10D samples demonstrated lower values of G', G'', and higher values tan δ at the oil-water interface as pressure increased, thereby promoting the formation of less viscoelastic structures. M-7D sample, characterized by lower content of α-helix structures, resulted in an observable redshift in the NH and CO groups of the protein. Molecular docking analysis affirmed that M-7D sample exhibited a lower absolute binding energy value, indicating stronger interaction with the protein compared to other samples, ultimately contributing to the unstable interfacial membrane formed.

Matched MeSH terms: Molecular Docking Simulation

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