Exploring the natural products chemical space to abrogate the F3L-dsRNA interface of monkeypox virus to enhance the immune responses using molecular screening and free energy calculations

Frontiers in Pharmacology, Год журнала: 2024, Номер 14

Опубликована: Янв. 10, 2024

Amid the ongoing monkeypox outbreak, there is an urgent need for rapid development of effective therapeutic interventions capable countering immune evasion mechanisms employed by virus (MPXV). The strategy involves binding F3L protein to dsRNA, resulting in diminished interferon (IFN) production. Consequently, our current research focuses on utilizing virtual drug screening techniques target RNA domain protein. Out 954 compounds within South African natural compound database, only four demonstrated notable docking scores: −6.55, −6.47, −6.37, and −6.35 kcal/mol. dissociation constant (KD) analysis revealed a stronger affinity top hits 1-4 (−5.34, −5.32, −5.29, −5.36 kcal/mol) with MPXV. All-atom simulations top-ranked 1 4 consistently exhibited stable dynamics, suggesting their potential interact effectively interface residues. This was further substantiated through analyses parameters such as radius gyration (Rg), Root Mean Square Fluctuation, hydrogen bonding. Cumulative assessments free energy confirmed top-performing candidates among all compounds, values −35.90, −52.74, −28.17, −32.11 kcal/mol 1-4, respectively. These results indicate that hit could hold significant promise advancing innovative therapies, suitability both vivo vitro experiments.

Язык: Английский

---

Unconventional strategy could be the future: From target to KRAS broad range treatment

Heliyon, Год журнала: 2024, Номер 10(9), С. e29739 - e29739

Опубликована: Апрель 18, 2024

The RAS gene family comprises genes that regulate cell growth and differentiation. KRAS, a member of this family, is often mutated in different cancers, resulting uncontrolled tumor development. Recent clinical trial results on KRAS inhibition NSCLC have defined the presence significant proportion patients resistant to direct G12C inhibition. co-mutations occurrence secondary resistance phenomena observed preclinical settings partly justify these poor results. In addition, all other non-G12C mutations currently remain without specific strategies. Evidence interactions between signaling TME suggests potential vitro efficacy immune checkpoint inhibitors. short paper, we reviewed most relevant data from recent conferences, with focus inhibitors mechanisms peri-tumor system.Commentary

Язык: Английский

---

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

Bioengineering, Год журнала: 2022, Номер 9(11), С. 633 - 633

Опубликована: Ноя. 1, 2022

Brucella suis, one of the causative agents brucellosis, is Gram-negative intracellular bacteria that may be found all over globe and it a significant facultative zoonotic pathogen in livestock. It adapt to phagocytic environment, reproduce, develop resistance harmful environments inside host cells, which crucial part life cycle making worldwide menace. The molecular underpinnings pathogenicity have been substantially elucidated due comprehensive methods such as proteomics. Therefore, we aim explore complete suis proteome prioritize novel proteins drug targets via subtractive proteo-genomics analysis, an effort conjecture existence distinct pathways development brucellosis. Consequently, 38 unique metabolic having 503 were observed while among these proteins, non-homologs (n = 421), essential 350), drug-like 114), virulence 45), 42), retrieved from suis. applied subsequent hierarchical shortlisting resulted protein, i.e., isocitrate lyase, act potential target, was finalized after extensive literature survey. interacting partners for shortlisted identified through STRING database. Moreover, structure-based studies also performed on lyase further analyze its function. For purpose, ~18,000 ZINC compounds screened identify new potent candidates against six compounds, ZINC95543764, ZINC02688148, ZINC20115475, ZINC04232055, ZINC04231816, ZINC04259566 potentially inhibit lyase. However, ADMET profiling showed fulfill properties except ZINC20115475 showing positive Ames activity; whereas, ZINC04259566, ZINC04231816 hepatoxicity no skin sensitization. In light parameters, recommend ZINC95543764 compound experimental studies. According present research, uses genomics, might serve therapeutic lead options eradicating brucellosis narrowed down.

Язык: Английский

---

Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

ACS Omega, Год журнала: 2023, Номер 8(25), С. 22809 - 22819

Опубликована: Июнь 12, 2023

Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. current work aims to evaluate a novel indazolone derivative against in vivo silico targets pain, neuropathy, inflammation. An (ID) was synthesized characterized using advanced spectroscopic techniques. Well-established animal models abdominal constriction, hot plate, tail immersion, carrageenan paw edema, Brewer's yeast-induced pyrexia were employed evaluating the potential ID at different doses (20-60 mg kg-1). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) pentylenetetrazole (PTZ), assess role GABAergic opioidergic processes. antineuropathic drug evaluated vincristine-induced neuropathic pain model. In studies performed any possible interactions with target sites like cyclooxygenases (COX-I/II), GABAA, receptors. This study revealed that selected (doses 20-60 kg-1) efficiently hampered chemically thermally induced nociceptive responses, producing significant anti-inflammatory antipyretic effects. These effects produced by dose-dependent (i.e., kg-1 p range 0.001-0.01) comparison standards (p < 0.001). Antagonistic NLX (1.0 PTZ (15.0 involvement mechanism rather than mechanism. showed promising anti-static allodynia well. preferential binding According results investigation, may serve future therapeutic agent treatment pyrexia, chemotherapy-induced inflammatory pain.

Язык: Английский

---

An extensive pharmacological evaluation of novel anti-nociceptive and IL-6 targeted anti-inflammatory guaiane-type sesquiterpenoids from Cinnamomum migao H. W. Li through in-depth in-vitro, ADMET, and molecular docking studies

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 164, С. 114946 - 114946

Опубликована: Май 29, 2023

Guaiane-type sesquiterpenoids are most prevalent in the genus Cinnamomum. Hence this study investigates structures, anti-nociceptive and IL-6 targeted anti-inflammatory potential of three novels C-14 guaiane-type two new monoterpenoids, isolated from Cinnamomum migao. The structures were precisely confirmed characterized through modern chromatographic spectroscopic techniques HRESIMS, 1D NMR, 2D experimental circular dichroism (ECD), calculated (ECD). Novel 1 2 exhibited significant activities against NO production pro-inflammatory cytokines. Their IC50 values determined as 9.52 13.42 μΜ mRNA, respectively. Similarly, subcutaneous injection n-BuT EA extracts showed a dose-dependent suppression formalin-induced tonic biting/licking responses during antinociceptive phase. Furthermore, absorption, distribution, metabolism, excretion, toxicity (ADMET) analysis displayed that both compounds have high level GIT with zone safety for cardiac hepatotoxicity no inhibition cytochromes. In addition, molecular docking simulation studies strengthen sesquiterpene which good binding affinity protein. Overall inclusive results newly C. migao will provide evidence traditional use species to treat inflammation nociception.

Язык: Английский

---

Phytochemical analysis, radical scavenging and glioblastoma U87 cells toxicity studies of stem bark of buckthorn (Rhamnus pentapomica R. Parker)

BMC Complementary Medicine and Therapies, Год журнала: 2024, Номер 24(1)

Опубликована: Янв. 2, 2024

Abstract Background During the past two decades, correlation between oxidative stress and a variety of serious illnesses such as atherosclerosis, chronic obstructive pulmonary disease (COPD), Alzheimer (AD) cancer has been established. Medicinal plants their derived phytochemicals have proven efficacy against free radicals associated diseases. The current work was aimed to evaluate phytochemical constituents Rhamnus pentapomica R. Parker via Gas Chromatography-Mass Spectrometry (GC–MS) its antioxidant anti-glioblastoma potentials. Methods bioactive compounds were analysed in stem bark extracts by GC–MS analysis, effects following standard procedures. extracted with 80% methanol for 14 days get crude methanolic extract (Rp.Cme) followed polarity directed fractionation using solvents including ethyl acetate, chloroform, butanol acetate fraction (Rp.EtAc), chloroform (Rp.Chf) (Rp.Bt) respectively. Antioxidant assay performed DPPH cell viability U87 glioblastoma lines MTT assay. Results In GC-MS thirty-one detected Rp.Cme, 22 Rp.Chf, 24 Rp.EtAc 18 Rp.Bt. Among identified 9-Octadecenoic acid (Z)-methyl ester (7.73%), Octasiloxane (5.13%) Heptasiloxane (5.13%), Hexadecanoic acid, methyl (3.76%) Pentadecanoic 14-methyl-, Ester highly abundant.. Benzene, 1,3-dimethyl- (3.24%) 1,3-dimethyl-(11.29%) abundant compounds. studies revealed that Rp.Cme exhibit considerable potentials IC 50 values 153.53 μg/ml 169.62 Both fractions also effective cells 147.64 76.41ug/ml Conclusion Phytochemical analysis presence important metabolites which might be active cells. Various samples plant exhibited warranting further detailed studies.

Язык: Английский

---

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

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер unknown, С. 1 - 13

Опубликована: Окт. 10, 2023

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

Язык: Английский

---

In silico exploration of the potential inhibitory activities of in-house and ZINC database lead compounds against alpha-glucosidase using structure-based virtual screening and molecular dynamics simulation approach

Journal of Biomolecular Structure and Dynamics, Год журнала: 2024, Номер unknown, С. 1 - 11

Опубликована: Янв. 31, 2024

Inhibitors of α-glucosidase have been used to treat type-2 diabetes (T2DM) by preventing the breakdown carbohydrates into glucose and prevent enhancing conversion. Structure-based virtual screening (SBVS) was generate novel chemical scaffold-ligand inhibitors. The databases were screened against receptor using SBVS molecular dynamics simulation (MDS) techniques in this study. Based on docking studies, three two compounds inhibitors chosen from a commercial database (ZINC) an In-house for study respectively. mode binding interactions selected later predicted their inhibitory potential. Finally, one out lead compound ZINC shortlisted based interactions. Furthermore, MDS post-MDS strategies refine validate leads along with reference acarbose/α-glucosidase. Hits' ability inhibit SBVS, indicating that these good activities. inhibitor's structure may serve as templates design inhibitors, vitro testing confirm anti-diabetic potential is necessary. These insights can help rationally new effective drugs.

Язык: Английский

---

Molecular screening of phytocompounds targeting the interface between influenza A NS1 and TRIM25 to enhance host immune responses

Journal of Infection and Public Health, Год журнала: 2024, Номер 17(7), С. 102448 - 102448

Опубликована: Май 10, 2024

Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza virus's NS1 hinders this process binding TRIM25, disrupting its association with and preventing downstream signalling, contributing evasion of immune response. In our study we used structural-based drug designing, molecular simulation, free energy approaches identify potent phytocompounds from various natural product databases (>100,000 compounds) able inhibit screening identified EA-8411902 EA-19951545 East African Natural Products Database, NA-390261 NA-71 North SA-65230 SA- 4477104 South Compounds NEA- 361 4524784 North-East TCM-4444713 TCM-6056 Traditional Chinese Medicines Database top hits. docking energies results revealed that these compounds have high affinity specific active site residues (Leu95, Ser99, Tyr89) involved interaction Additionally, analysis structural dynamics, energy, dissociation constants demonstrates notably stronger protein. Moreover, all selected exhibit exceptional ADMET properties, including water solubility, gastrointestinal absorption, an absence hepatotoxicity, while adhering Lipinski's rule. Our simulation findings highlight demonstrate NS1-TRIM25 interaction, adhere drug-likeness criteria, thus presenting promising candidates further development antiviral agents against

Язык: Английский

---

In Silico Targeting of Fascin Protein for Cancer Therapy: Benchmarking, Virtual Screening and Molecular Dynamics Approaches

Molecules, Год журнала: 2023, Номер 28(3), С. 1296 - 1296

Опубликована: Янв. 29, 2023

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking binding sites considered a vital target for antimetastatic drugs. This inspired us to find new site blockers. First, we built active compound set by collecting reported small molecules Fascin's 2. Consequently, high-quality decoys was generated employing DEKOIS 2.0 protocol be applied conducting the benchmarking analysis against selected structures. Four docking programs, MOE, AutoDock Vina, VinaXB, PLANTS were evaluated study. All tools indicated better-than-random performance reflected their pROC-AUC values crystal structure (PDB: ID 6I18). Interestingly, exhibited best screening recognized potent actives at early enrichment. Accordingly, utilized prospective virtual effort repurposing FDA-approved drugs (DrugBank database) natural products (NANPDB). Further assessment via molecular dynamics simulations 100 ns endorsed Remdesivir (DrugBank) NANPDB3 (NANPDB) as potential binders In conclusion, this study delivers model implementing customized benchmark enhance VS success rate targets cancer therapies.

Язык: Английский

---