Repositioning of Furin inhibitors as potential drugs against SARS-CoV-2 through computational approaches

Journal of Biomolecular Structure and Dynamics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 15

Published: Jan. 24, 2025

The recent spread of SARS-CoV-2 has led to serious concerns about newly emerging infectious coronaviruses. Drug repurposing is a practical method for rapid development antiviral agents. viral spike protein binds its major receptor ACE2 promote membrane fusion. Following the entry process, further activated by cellular proteases such as TMPRSS2 and Furin into human cells. A crucial factor in preventing from entering target cells using HIV-1 fusion inhibitors similarity between mechanisms HIV-1. In this investigation, CMK, Luteolin, Naphthofluorescein were selected understand molecular mode interactions binding energy with these experimental inhibitors. affinity three was verified docking studies. scores Luteolin are -7.4 kcal/mol, -9.3 -10.7 respectively. Therefore, compounds subjected MD, drug-likeness, ADMET, MM-PBSA analysis. According results 200 ns MD simulation, all tested show stability complex can be employed promising targeting protease. addition, pharmacokinetic analysis revealed that possess favorable drug-likeness properties. Thus, study helps evaluation use novel drugs against SARS-CoV-2.

Language: Английский

---

Docking and other computing tools in drug design against SARS-CoV-2

SAR and QSAR in environmental research, Journal Year: 2024, Volume and Issue: 35(2), P. 91 - 136

Published: Feb. 1, 2024

The use of computer simulation methods has become an indispensable component in identifying drugs against the SARS-CoV-2 coronavirus. There is a huge body literature on application molecular modelling to predict inhibitors target proteins SARS-CoV-2. To keep our review clear and readable, we limited ourselves primarily works that computational find test predicted compounds experimentally either protein assays or cell culture with live Some containing results experimental discovery corresponding without using are included as examples success. Also, some confirmations also if they attract attention by databases used. This collects studies various methods: docking, dynamics, quantum mechanics, machine learning, others. Most these based other used mainly for post-processing select best among those found through docking. Simulation presented concisely, information provided organic can be useful virtual screening, itself structured accordance coronavirus proteins.

Language: Английский

---

Targeting small druggable compounds against 3RZE histamine H1 receptor as potential of anti-allergic drug applying molecular modeling approach

Future Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 10(1)

Published: June 6, 2024

Abstract Background Allergic disorders, prevalent global health concerns, afflict a substantial portion of the world’s population. These maladies result from an exaggerated immune system response to ordinarily innocuous substances, such as pollen, dust mites, and specific dietary components. Clinical manifestations this heightened include itching, swelling, respiratory impairment, often accompanied by releasing mediators like histamine. The pathophysiological mechanisms allergy disorders are intricate, arising complex interplay between genetic environmental factors. While clinical presentations may vary, all conditions share common foundation in dysregulated allergens. Result current aim study was identify innovative anti-allergic agents capable inhibiting histamine effectively mitigating allergic reactions utilizing computer-aided drug design approach discovery studio (DS) 2022 v 23.1.1 package. overarching identifying potential candidates targeting active site within H1 receptor complex; therefore, collection 4000 small druggable compounds curated ZINC, PubChem, DRUG BANK databases sources. Four appeared promising after assessing docking scores binding energies. Notably, Compound ID 34154, recognized tymazoline, showed highest affinity for 3RZE, suggesting it be most choice more research. Further chemoinformatic ADMET (absorption, distribution, metabolism, excretion, toxicity) analyses were conducted assess drug-like qualities chosen molecule. In addition, bioisosteric substitution techniques employed enhance tymazoline’s characteristics. Conclusion Tymazoline shows strong with 3RZE verified drug-likeness criteria inhibit disorders. Furthermore, molecular dynamics (MD) studies corroborated agent, demonstrating contact ligand that is well defined stable.

Language: Английский

---

Impact of Some Natural and Artificial Sweeteners Consumption on Different Hormonal Levels and Inflammatory Cytokines in Male Rats: In Vivo and In Silico Studies

ACS Omega, Journal Year: 2024, Volume and Issue: 9(28), P. 30364 - 30380

Published: July 1, 2024

Substituting sugar with noncaloric sweeteners prevents overweight and diabetes development. They come in two types: artificial, like aspartame sucralose, natural, such as sorbitol. This research aimed to assess the effects of sucrose these on nutritional parameters, hematological hormones, anti- pro-inflammatory cytokines male rats. Thirty rats had been separated into five groups. The results showed highest significant increase body weight gain, total food intake, feed efficiency noticed group followed by sucrose, sorbitol, respectively. In contrast RBCs platelets, all significantly reduced hemoglobin level, Hct %, WBC count. decline glycoproteins, steroids, T3, T4 hormones a dramatic elevation thyroid stimulating hormone, eicosanoid, amine compared control group. A vigorous proinflammatory cytokine levels was observed group, sorbitol Aspartame has docking scores when studying interactions target protein associated or using silico molecular docking, best absorption, distribution, metabolism, elimination, toxicity properties remaining sweeteners.

Language: Английский

---

Screening of phytochemicals from Clerodendrum inerme (L.) Gaertn as potential anti-breast cancer compounds targeting EGFR: an in-silico approach

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 43

Published: Dec. 23, 2023

Breast cancer (BC) is the most prevalent malignancy among women around world. The epidermal growth factor receptor (EGFR) a tyrosine kinase (RTK) of ErbB/HER family. It essential for triggering cellular signaling cascades that control cell and survival. However, perturbations in EGFR lead to development progression. Hence, regarded as prominent therapeutic target breast cancer. Therefore, current investigation, was targeted with phytochemicals from Clerodendrum inerme (L.) Gaertn (C. inerme). A total 121 identified by gas chromatography-mass spectrometry (GC-MS) analysis were screened against through molecular docking, ADMET analyses (Absorption, Distribution, Metabolism, Excretion, Toxicity), PASS predictions, dynamics simulation, which revealed three potential hit compounds CIDs 10586 [i.e. alpha-bisabolol (−6.4 kcal/mol)], 550281 2,(4,4-Trimethyl-3-hydroxymethyl-5a-(3-methyl-but-2-enyl)-cyclohexene) (−6.5 161271 salvigenin (−7.4 kcal/mol)]. FDA-approved drug gefitinib used compare inhibitory effects phytochemicals. top selected exhibited good properties obeyed Lipinski's rule five (ROF). docking showed best formed bonds key residue Met 793. Furthermore, mechanics generalized born surface area (MMGBSA) calculations, normal mode validated binding affinity also strong stability compactness at docked site. Additionally, DFT DOS done study reactivity further validate These results suggest possess high can treat vitro vivo investigations are warranted towards these constituents into novel anti-cancer drugs.

Language: Английский

---

Annonaceous acetogenins as promising DNA methylation inhibitors to prevent and treat leukemogenesis – an in silico approach

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 14

Published: Dec. 27, 2023

Leukemia is a haematological malignancy affecting blood and bone marrow, ranking 10th among the other common cancers. DNA methylation an epigenetic dysregulation that plays critical role in leukemogenesis. methyltransferases (DNMTs) such as DNMT1, DNMT3A DNMT3B are key enzymes catalysing methylation. Inhibition of DNMT1 with secondary metabolites from medicinal plants helps reverse The present study focuses on inhibiting protein (PDB ID: 3PTA) annonaceous acetogenins through in-silico studies. docking molecular dynamic (MD) simulation was carried out using Schrödinger Maestro Desmond, respectively. These compounds' drug likeliness, ADMET properties bioactivity scores were analysed. About 76 different chosen for this study, which 17 showed highest binding energy range −8.312 to −10.266 kcal/mol. compounds negative found be annohexocin (-10.266 kcal/mol), isoannonacinone (-10.209 kcal/mol) annonacin (-9.839 kcal/mol). MD results reveal remains stable throughout time 100 ns also binds catalytic domain protein. From above results, it can concluded has potential inhibit process prevent

Language: Английский

---

Bioprospecting of potential inhibitors of 5alpha reductase 2 inhibitors from relevant ethno-pharmacological plants via in silico techniques

Scientific African, Journal Year: 2024, Volume and Issue: 25, P. e02264 - e02264

Published: May 28, 2024

Approximately 60% of men globally over the age 50 experience a diminished quality life as result benign prostatic hyperplasia (BPH). Consequently, while national direct cost for managing BPH is hovering around $4 billion in USA, individual medications estimated at $1536 and $425 annually USA Ghana, respectively. Due to chemotherapeutic drawbacks treatment, concerted effort urgently needed find new chemotypes with novel mechanism action combat disease. This research aims employ computational techniques identify compounds from ethno-pharmacological plants Ghana treating BPH. Altogether, 250 natural products Croton membranaceus, Heliotropium angiospermum, Annona muricata, Serenoa repens, Cissus quadrangularis, Tribulus terrestrials, Vernonia amagdalina Momordica foetida Ghanaian origin were virtually screened against 5alpha reductase 2 (5aR2), primary drug target implicated parthenogenesis Out 254 docked, three (A, B C) showed binding energy lower than testosterone (-10.4 kcal/mol), main substrate comparative finasteride (-11.7 one drugs currently used Molecular docking dynamics simulations studies revealed Leu224 be critical ligand complex stability. The pharmacological physicochemical profiles show possess good pharmacodynamics negligible toxicities. While A, C, G, H, I J were, respectively, predicted treat prostate disorders Pa (0.909, 0.221, 0.743, 0.729, 0.978, 0.443) Pi (0.003, 0.132, 0.005,0.005, 0.002, 0.016), that B, D, I, found associated inhibition (0.840, 0.102, 0.097, 0.377, 0.123, 0.909, 0.201) (0.001, 0.075, 0.089, 0.003, 0.036, 0.001, 0.004) These lead-like possessing plausible moieties putative 5aR2 inhibitory potential need further experimental validation via vitro studies.

Language: Английский

---

Mining for Potent Inhibitors through Artificial Intelligence and Physics: A Unified Methodology for Ligand Based and Structure Based Drug Design

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: unknown

Published: June 6, 2024

Determining the viability of a new drug molecule is time- and resource-intensive task that makes computer-aided assessments vital approach to rapid discovery. Here we develop machine learning algorithm, iMiner, generates novel inhibitor molecules for target proteins by combining deep reinforcement with real-time 3D molecular docking using AutoDock Vina, thereby simultaneously creating chemical novelty while constraining shape compatibility active sites. Moreover, through use various types reward functions, have introduced in generative tasks such as similarity ligand, grown from known protein bound fragments, creation enforce interactions residues site. The iMiner algorithm embedded composite workflow filters out Pan-assay interference compounds, Lipinski rule violations, uncommon structures medicinal chemistry, poor synthetic accessibility options cross-validation against other scoring functions automation dynamics simulation measure pose stability. We also allow users define set rules they would like exclude during training process postfiltering steps. Because our relies only on structure protein, can be easily adapted future development inhibitors or small therapeutics any protein.

Language: Английский

---

<i>Thymus Algeriensis</i> Essential Oil: Phytochemical Investigation, Bactericidal Activity, Synergistic Effect with Colistin and Molecular Docking Analysis Against Gram-Negative Bacteria Resistant to Colistin

Published: Jan. 1, 2024

Due to the increasing resistance' prevalence last line of antibiotics such as colistin and rising threat multi drug resistant bacteria, it is crucial find alternative therapeutic options. The current study focuses on evaluating antibacterial activities alone in combination with Thymus algeriensis essential oil (TA-EO) against colistin-resistant Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli co-harboring mcr-1 gene. GC/MS was used determinate chemical composition TA-EO. Disc diffusion microdilution techniques were evaluate antimicrobial Synergism between TA-EO evaluated by checkerboard assay. major compound docked known enzymes involved resistance biosynthesis (PDB IDs: 5GOV, 5GRR, 2E98, 1X06, 7KH7). revealed that carvacrol chemotype (67.94%). showed remarkable all Gram-negative bacterial strains diameter inhibition zones varied 30 50 mm, ratio CMI/CMB equal 1 for majority isolates. Interestingly, synergism gene (FICI˂1), reduced MIC 16- 512-fold those 4- fold. docking demonstrated had high binding free energies MCR-1, a phosphoethanolamine transferase extracellular domain ID: 5GOV), its catalytic 5GRR), undecaprenyl pyrophosphate synthase complex magnesium which implicated peptidoglycan 1X06). These results seem argue benefit effect use derivative constituent bactericidal agent or treat infections caused bacteria colistin.

Language: Английский

---

Computational design of CDK1 inhibitors with enhanced target affinity and drug-likeness using deep-learning framework

Heliyon, Journal Year: 2024, Volume and Issue: 10(22), P. e40345 - e40345

Published: Nov. 1, 2024

Cyclin Dependent Kinase 1 (CDK1) plays a crucial role in cell cycle regulation, and dysregulation of its activity has been implicated various cancers. Although several CDK1 inhibitors are currently clinical trials, none have yet approved for therapeutic use. This research utilized deep learning techniques, specifically Recurrent Neural Networks with Long Short-Term Memory (LSTM), to generate potential inhibitors. Molecular docking, evaluation molecular properties, dynamics simulations were conducted identify the most promising candidates. The results showed that generated ligands exhibited substantial improvements target affinity drug-likeness. docking had an average binding -10.65 ± 0.877 kcal/mol towards CDK1. Quantitative Estimate Drug-likeness (QED) values averaged 0.733 0.10, significantly higher than 0.547 0.15 observed known (p < 0.001). further confirmed stability favorable interactions selected complex. identification novel improved affinities drug-likeness properties could potentially fill gap ongoing development CDK However, it is imperative note extensive experimental validation required prior advancing these subsequent stages drug development.

Language: Английский

---