ADMET Analysis Research Articles

Isolation and spectroscopic characterization of anticancer phytochemicals from Artemisia laciniata: a combined experimental and theoretical investigation using ADMET analysis and in silico molecular docking simulation against key cancer targets.

Artemisia laciniata, a high-altitude medicinal herb, possesses diverse therapeutic properties. This study conducted a comprehensive phytochemical analysis of the whole plant, leading to the isolation of 15 secondary metabolites (1-15) across various classes: flavonoids (1-6), triterpenoids (7, 8), sesquiterpenoid lactones (9, 10) and furanocoumarins (11, 12) along with three steroids (13-15). These compounds were characterized using NMR (1HNMR,13C NMR, 2D NMR), IR, HRMS and UV-VIS. All were reported for the first time from this plant, with compound 10 being a novel natural product. In-vitro antitumor activity was evaluated against lung (A549), colon (HCT116), prostate (PC3) and breast (T47D) cancer cell lines.Compounds 3, 4, 6, 7, 8 and 10demonstrated significant antitumor activity, with compounds 3, 7 and 8 exhibiting IC50 values 8 and 28 µM. In silico molecular docking and ADMET analysis were conducted to assess pharmacokinetics and pharmacodynamics, revealing strong binding affinities of compounds 3, 6, and 7, particularly with PD-L1, highlighting their potential to target multiple cancer-related pathways. This study concludes that A. laciniata contains potent anticancer phytochemicals that target key proteins involved in cancer development, as demonstrated by MTT assay results.

The potential of Curcuma longa L. bioactive compounds as RSK inhibitors for the treatment of prostate cancer: in silico study

BackgroundThe second most seen malignancy occurrence among males is prostate cancer. The p90 ribosomal s6 kinase (RSK) has attracted increased attention due to its overexpression in cancer cells, especially prostate cancer cells. Significant progress has been made recently to develop RSK inhibitors to treat prostate cancer, but these efforts have shown limited success.MethodsMolecular docking and other computational analysis procedures using the Schrodinger suite were used to predict in silico the ability of bioactive compounds from turmeric (Curcuma longa) to bind effectively to RSK as potent inhibitors. Forty-three (43) selected compounds from turmeric were screened against RSK. After the molecular and induced-fit docking, the hit compounds were later subjected to ADMET, MMGBSA, and QSAR analyses using the Schrödinger suite.ResultsFive bioactive compounds may be possible lead drugs for the treatment of prostate cancer because they have the lowest binding energies, ranging from − 9.0 kcal/mol to − 11.00 kcal/mol, and have better pharmacokinetic qualities than the standard drugs docetaxel, enzalutamide, and abiraterone. The ligand and receptor had induced fit scores of − 8.511, − 6.977, − 8.671, − 9.548, and − 8.287 for 3-O-caffeoylquinic acid, 8-hydroxyl-ar-turmeron, bisdemethoxycurcumin, Curcumin II, and demethoxycurcumin, respectively. These hit compounds after ADMET prediction do not violate Lipinski's rule of five.ConclusionThe work suggested that turmeric phytocompounds are effective RSK inhibitors for prostate cancer treatment. Further in vivo and in vitro investigations can confirm these findings.

Essential oil composition, invitro antidiabetic, cytotoxicity, antimicrobial, antioxidant activity, and in silico molecular modeling analysis of secondary metabolites from Justicia schimperiana.

Justicia schimperiana, known as "Dhumuugaa" in Afan Oromo and "Sensel" or "Smiza" in Amharic, is traditionally used to treat ailments such as scabies, fever, asthma, diarrhea, malaria, and more. This study explored the chemical composition and biological activity of its extracts and isolated compounds. The essential oils were extracted using the hydrodistillation method, and their chemical composition was evaluated using GC-MS. GC-MS analysis identified 54 and 52 chemical components in the essential oils (EOs) from roots and leaves, respectively. The structures of the isolated compounds have been identified using 1D and 2D-NMR techniques. Six compounds- β-sitosterol (1), 5-methoxy durmillone (2), trans-resveratrol (3), tricuspidatol A (4), kaempferol-3-O-α-rhamnopyranoside (5), and kaempferol-3-O-rutinoside (6)- were isolated from the root extracts and reported for the first time in this species. The antimicrobial activity was evaluated using the broth microdilution technique. EOs extracts showed significant antibacterial activity, particularly against Staphylococcus aureus, Streptococcus agalactiae, while compound 6 showed potent activity with an MIC of 0.25 μg/mL. The antioxidant activity revealed strong radical scavenging for compounds 5 and 6, with extracts also demonstrating significant α-amylase inhibitory effects and moderate cytotoxicity against the MCF-7 cell line. Molecular docking and ADMET analysis highlighted compounds 5 and 6 as promising therapeutic agent. These findings highlight the medicinal potential of J.schimperiana roots, warranting further exploration.

Identification of DDR1 Inhibitors from Marine Compound Library Based on Pharmacophore Model and Scaffold Hopping

Ulcerative colitis (UC) is a chronic inflammatory condition that affects the intestines. Research has shown that reducing the activity of DDR1 can help maintain intestinal barrier function in UC, making DDR1 a promising target for treatment. However, the development of DDR1 inhibitors as drugs has been hindered by issues such as toxicity and poor binding stability. As a result, there are currently no DDR1-targeting drugs available for clinical use, highlighting the need for new inhibitors. In a recent study, a dataset of 85 DDR1 inhibitors was analyzed to identify key characteristics for effective inhibition. A pharmacophore model was constructed and validated to screen a library of marine natural products for potential DDR1 inhibitors. Through high-throughput virtual screening and precise docking, 17 promising compounds were identified from a pool of over 52,000 molecules in the marine database. To improve binding affinity and reduce potential toxicity, scaffold hopping was employed to modify the 17 compounds, resulting in the generation of 1070 new compounds. These new compounds were further evaluated through docking and ADMET analysis, leading to the identification of three compounds—39713a, 34346a, and 34419a—with superior predicted activity and drug-like properties compared to the original 17 compounds. Further analysis showed that the binding free energy values of the three candidate compounds were less than −12.200 kcal/mol, which was similar to or better than −12.377 kcal/mol of the known positive compound VU6015929, and the drug-like properties were better than those of the positive compounds. Molecular dynamics simulations were then conducted on these three candidate compounds, confirming their stable interactions with the target protein. In conclusion, compounds 39713a, 34346a, and 34419a show promise as potential DDR1 inhibitors for the treatment of ulcerative colitis.

Computational evaluation on spectroscopic (FT-IR, Raman), electronic and biological, and NLO properties of cirsilineol by DFT, ADMET, and molecular docking method

Cirsilineol is a natural product that has pharmacological characteristics and is used to prevent the growth of cancer. This study aims to investigate the spectroscopic, electronic, and biological properties of drugs and predict their suitability for drug-like candidates to inhibit prostate cancer. The computational evaluation was performed with density functional theory (DFT) at B3LYP/6−311++G(d,p) level of theory and drug-like characteristics rendered from ADMET analysis. Spectral measurement for IR and Raman provided evidence of intra-molecular hydrogen bonding of the OH group in ring R1. The electronic transition properties of the title compound were determined using TD-DFT with a polarized continuum model in solvent ethanol, resulting in a blue shift in absorption wavelength. The electrostatic potential mapped with the van der Wall surface predicted effective electrophiles and nucleophiles, allowing for the layout of intra- and intermolecular hydrogen bonds. The pharmacological properties of cirsilineol determined by ADMED analysis confirmed that it is non-toxic. To assess the biological performance of cirsilineol, molecular docking was performed with protein codes 1E3G and 1GS4, which showed inhibition action with binding affinity −7.7 and −7.8 kcal/mol, respectively.

Targeting Antibacterial Resistance: Computational Exploration of Bioactive Compounds in Dipsacus asper Integrating Docking, ADMET Analysis, and Molecular Dynamics Simulations

Natural compounds derived from plants offer a sustainable and promising solution to the global challenge of antimicrobial resistance. This study focuses on Dipsacus asper (D. asper), a plant traditionally used in Chinese medicine, and investigates its bioactive potential to identify novel antibacterial agents. Leveraging comprehensive in‐silico analyses, 44 compounds previously isolated from D. asper were evaluated for their binding affinities against four key bacterial proteins: DNA gyrase B, Tyrosyl‐tRNA‐synthetase, Penicillin Binding Protein 2X (PBP2X), and Penicillin Binding Protein 4 (PBP4). This integrated approach, combining molecular docking, ADMET profiling, DFT, and MESP studies, identified Dipsalignan, Cantleyoside, Triplostoside A, and Dipsanoside N as leading candidates. Dipsalignan demonstrated superior bioavailability and distinct electronic properties influencing its reactivity. Molecular dynamics (MD) simulations validated the stability of protein‐ligand interactions, with RMSD and RMSF analyses confirming equilibrium under physiological conditions. Binding free energy calculations revealed that van der Waals and hydrophobic interactions are critical in enhancing inhibitory potential. Biological significance was evident as the computationally identified compounds align with essential criteria for effective antibacterial agents, warranting further in vitro and in vivo studies. This research underscores the potential of D. asper‐derived compounds to address antimicrobial resistance and presents a robust framework for discovering plant‐based antibacterial agents.

Discovery of SARS-CoV-2 Mpro inhibitors through rational design of novel fluorinated 1,3,4-oxadiazole amide derivatives: An in-silico study.

The main protease (Mpro) of SARS-CoV-2 is an evolutionarily conserved drug discovery target. The present study mainly focused on chemoinformatics computational methods to investigate the efficacy of our newly designed trifluoromethyl-1,3,4-oxadiazole amide derivatives as SARS-CoV-2 Mpro inhibitors. Drug-likeness ADMET analysis, molecular docking simulation, density functional theory (DFT) and molecular dynamics simulation methods were included. A comprehensive drug-likeness analysis was performed on the 14 newly designed compounds (1a~1n), and these series of small molecules inhibitors showed potential anti-SARS-CoV-2 activity. In order to reveal the mechanism of drug interaction, these novel compounds were classified by structure and molecular docking simulations were performed. The results showed good interactions and identified the key amino acid residue GLY-143. Further DFT analysis using B3LYP-D3BJ functional and 6-311 + + G (d, p) basis set was performed to optimize the optimal configuration of the Mpro inhibitors, and the infrared spectrum of the vibration frequency was analyzed to clearly understand the structure and stability of the drug. These new series of small molecule inhibitors studied in this work will provide the necessary theoretical basis for the synthesis and activity evaluation of novel SARS-CoV-2 Mpro inhibitors.

Evaluation of methoxyflavones as dengue NS2B-NS3 protease inhibitors: an in silico and in vitro studies.

Dengue is one of the most prevalent viruses transmitted by the Aedes aegypti mosquitoes. Currently, no specific medication is available to treat dengue diseases. The NS2B-NS3 protease is vital during post-translational processing, which is a key target in this study. Due to methoxy group substitution, methoxyflavones are more bioavailable and metabolically stable than hydroxylated flavones. To date, research on the anti-dengue activity of methoxyflavones is limited. Hence, this work aims to determine the inhibitory activity of methoxyflavones against the dengue NS2B-NS3. Methoxyflavones derivatives were screened using molecular docking. The result showed a strong binding interaction of compound 1 and compound 2 with NS2B-NS3 protease. Both compounds exhibited comparable binding energy as the reference compound, quercetin, with values lower than - 8.1kcal/mol. Molecular dynamics simulation using GROMACS revealed the stability and stiffness of the complexes over a 100ns time scale. In addition, an in vitro assay for NS2B-NS3 protease inhibition revealed inhibitory effects of compounds 1 and 2 with IC50 values of 316.80µM and 463.30µM, respectively. The ADMET analyses showed favorable pharmacokinetics profiles that comply with Lipinski's Rule of Five. Collectively, our findings suggest that compounds 1 and 2 inhibit dengue NS2B-NS3 activity. These findings hold promise of methoxyflavones as starting compounds for potential dengue treatment, highlighting the need for further investigation.

Adenocarpine, Marmesin, and Lycocernuine from Ficus benjamina as Promising Inhibitors of Aldose Reductase in Diabetes: A Bioinformatics-Guided Approach.

Diabetes affects approximately 422 million people worldwide, leading to 1.5 million deaths annually and causing severe complications such as kidney failure, neuropathy, and cardiovascular disease. Aldose reductase (AR), a key enzyme in the polyol pathway, is an important therapeutic target for managing these complications. The high cost, severe side effects, and rising drug resistance in traditional diabetes treatments underscore the urgent need for novel AR-targeting antidiabetic agents. Ficus benjamina used in traditional medicine demonstrates promising potential for diabetes management. This study investigated the antidiabetic potential of F. benjamina phytocompounds targeting AR receptor employing a structure-based drug design approach to identify potential antidiabetic drug agents. Using molecular docking, ADMET analysis, molecular dynamics (MD) simulation, MM/GBSA, MM/PBSA, and DFT calculations, we identified three promising lead compounds: adenocarpine (- 9.2kcal/mol), marmesin (- 8.8kcal/mol), and lycocernuine (- 8.4kcal/mol). These compounds presented favorable pharmacokinetic, pharmacodynamic, and toxicity profiles, with a 500-ns MD simulation confirming their stability, supported by PCA and Gibbs FEL analysis. MM/GBSA study identified adenocarpine (- 72.53kcal/mol) as the best compound, outperforming marmesin (- 70kcal/mol) and lycocernuine (- 61.95kcal/mol). DFT analysis revealed that adenocarpine exhibited the highest molecular reactivity (3.914eV), while lycocernuine demonstrated the greatest kinetic stability (6.377eV). Marmesin and lycocernuine showed increased reactivity upon transitioning from the free states (4.441eV and 6.377eV, respectively) to the bound states (4.359eV and 6.231eV, respectively). These results could lead to the development of adenocarpine, marmesin, and lycocernuine as novel drug candidates for diabetes, warranting further in vitro and in vivo validation.

In silico Comparative Study of the Anti‐Cancer Potential of Inhibitors of Glucose‐6‐Phosphate Dehydrogenase Enzyme Using ADMET Analysis, Molecular Docking, and Molecular Dynamic Simulation

In silico Comparative Study of the Anti‐Cancer Potential of Inhibitors of Glucose‐6‐Phosphate Dehydrogenase Enzyme Using ADMET Analysis, Molecular Docking, and Molecular Dynamic Simulation

An in-depth study of indolone derivatives as potential lung cancer treatment

Lung cancer is a type of cancer that begins in the lungs and is one of the leading causes of cancer-related deaths worldwide. Herein an attempt to explore the relationship between the properties of indolone derivatives and their anticancer activity was investigated, implementing in silico approaches. Four indolone derivatives with the highest anticancer potential were selected to evaluate their pharmacological properties. The ADMET analysis revealed that these compounds exhibited favourable drug-like properties, meeting nearly all the key pharmacological criteria required for potential therapeutic agents. Molecular docking studies of the most active compounds revealed strong interactions with critical amino acid residues in the PDK1 receptor’s binding site, underscoring their potential as effective PDK1 inhibitors. In addition, 200 ns molecular dynamics (MD) simulations of two R and S configurations validated the stability of the ligand-receptor complexes, with minimal structural deviations observed throughout the simulation period. These comprehensive results highlight the potential of the selected indolone derivatives as viable drug candidates and provide a solid foundation for future optimization efforts aimed at developing novel PDK1 inhibitors for cancer therapy.

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

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

Exploring target selectivity in designing and identifying PI3Kα inhibitors for triple negative breast cancer with fragment-based and bioisosteric replacement approach

Triple-negative breast cancer (TNBC) is one of the most fatal malignancies in the world, accounting for 42% of all deaths due to metastasis. The significant development is hindered by the multi-drug resistance and poor patient compliance. PIK3CA gene mutation is one of the important causes of TNBC, which causes dysregulation of the cell cycle and cell proliferation. PI3Kα selective inhibition can decrease the TNBC by a significant level with minimal off-target effects. Novel compounds with high selectivity towards PI3Kα are crucial for treating TNBC. After extensive literature analysis, it was observed that fragment-based drug discovery, combined with structure-based virtual screening and bioisosteric replacement strategy, could provide a novel way for hit-to-lead optimization. The present study focussed on the fragment-based direct linking of 11269 moieties of the ChemDiv fragment library, - to generate novel moieties and further screened them using molecular docking, MMGBSA, and target selectivity analysis. Further, the top 2 moieties – Djh1 and Djh2 were selected after MMGBSA analysis and target selectivity prediction towards kinase. Further induced fit docking (IFD) analysis, DFT analysis, and MD simulation were employed to establish that – Djh1 and Djh2 could act as potential hit molecules for selective inhibition of PI3Kα. Further bioisosteric replacement, docking analysis, and target selectivity analysis were performed with the bioisosteres. The top two bioisosteres of Djh1 – Compound 10, Compound 06 represented excellent efficacy and selectivity towards PI3Kα in the treatment of TNBC after analysis of ADMET analysis. Further, in vitro and in vivo analysis might prove the effectiveness of the hit compounds.

Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study.

Background/Objectives: Kynurenine aminotransferase II (KAT-II) is a target for treating several diseases characterized by an excess of kynurenic acid (KYNA). Although KAT-II inactivators are available, they often lead to adverse side effects due to their irreversible inhibition mechanism. This study aimed to identify potent and safe inhibitors of KAT-II using computational and in vitro approaches. Methods: Virtual screening, MM/GBSA, and molecular dynamics simulations were conducted to identify the top drug candidates, followed by kinetic measurements and in vitro cytotoxicity evaluation. Results: The study showed that two compounds, herbacetin and (-)-Epicatechin exhibited the best scores. Their Glide docking scores are -8.66 kcal/mol and -8.16 kcal/mol, respectively, and their MM/GBSA binding energies are -50.30 kcal/mol and -51.35 kcal/mol, respectively. These scores are superior to those of the standard inhibitor, PF-04859989, which has docking scores of -7.12 kcal/mol and binding energy of -38.41 kcal/mol. ADMET analysis revealed that the selected compounds have favorable pharmacokinetic parameters, moderate bioavailability, and a safe toxicity profile, which supports their potential use. Further, the kinetic study showed that herbacetin and (-)-Epicatechin are reversible KAT-II inhibitors and exhibit a competitive inhibition mechanism. Their half-maximal inhibitory concentrations (IC50) are 5.98 ± 0.18 µM and 8.76 ± 0.76 µM, respectively. The MTT assay for cell toxicity indicated that the two compounds do not affect HepG2 cell viability at the necessary concentration for KAT-II inhibition. Conclusions: These results suggest that herbacetin and (-)-Epicatechin are suitable for KAT-II inhibition and are promising candidates for further development of KAT-II inhibitors.

Exploring the antifungal potential of Cannabis sativa-derived stilbenoids and cannabinoids against novel targets through in silico protein interaction profiling.

Cannabinoid and stilbenoid compounds derived from Cannabis sativa were screened against eight specific fungal protein targets to identify potential antifungal agents. The proteins investigated included Glycosylphosphatidylinositol (GPI), Enolase, Mannitol-2-dehydrogenase, GMP synthase, Dihydroorotate dehydrogenase (DHODH), Heat shock protein 90 homolog (Hsp90), Chitin Synthase 2 (CaChs2), and Mannitol-1-phosphate 5-dehydrogenase (M1P5DH), all of which play crucial roles in fungal survival and pathogenicity. This research evaluates the binding affinities and interaction profiles of selected cannabinoids and stilbenoids with these eight proteins using molecular docking and molecular dynamics simulations. The ligands with the highest binding affinities were identified, and their pharmacokinetic profiles were analyzed using ADMET analysis. The results indicate that GMP synthase exhibited the highest binding affinity with Cannabistilbene I (-9.1kcal/mol), suggesting hydrophobic solid interactions and multiple hydrogen bonds. Similarly, Chitin Synthase 2 demonstrated significant binding with Cannabistilbene I (-9.1kcal/mol). In contrast, ligands such as Cannabinolic acid and 8-hydroxycannabinolic acid exhibited moderate binding affinities, underscoring the variability in interaction strengths among different proteins. Despite promising in silico results, experimental validation is necessary to confirm therapeutic potential. This research lays a crucial foundation for future studies, emphasizing the importance of evaluating binding affinities, pharmacokinetic properties, and multi-target interactions to identify promising antifungal agents.

Preliminary Data on Silybum marianum Metabolites: Comprehensive Characterization, Antioxidant, Antidiabetic, Antimicrobial Activities, LC-MS/MS Profiling, and Predicted ADMET Analysis.

Silybum marianum extract, obtained via microwave-enhanced extraction, was evaluated for its antioxidant, antidiabetic, and antimicrobial activities to explore its therapeutic potential. The extraction was performed using microwave-enhanced techniques, and LC-MS/MS was employed to profile the metabolites in the extract. Total phenolic and flavonoid contents were quantified using spectrophotometric methods. Antioxidant activity was assessed using DPPH, ABTS, CUPRAC, Phenanthroline, and FRAP assays. Enzyme inhibition assays were conducted to evaluate antidiabetic activity against α-glucosidase and α-amylase. Antimicrobial activity was determined using the disc diffusion method, and in silico ADMET and drug-likeness analyses were performed for key metabolites. The extract contained 251.2 ± 1.2 mg GAE/g of total phenolics and 125.1 ± 1.6 mg QE/g of total flavonoids, with 33 metabolites identified, including phenolic acids, tannins, flavonoids, and flavolignans. Strong antioxidant activity was observed, with IC50 values of 19.2 ± 2.3 μg/mL (DPPH), 7.2 ± 1.7 μg/mL (ABTS), 22.2 ± 1.2 μg/mL (CUPRAC), 35.2 ± 1.8 μg/mL (Phenanthroline), and 24.1 ± 1.2 μg/mL (FRAP). Antidiabetic effects were significant, with IC50 values of 18.1 ± 1.7 μg/mL (α-glucosidase) and 26.5 ± 1.3 μg/mL (α-amylase). Antimicrobial activity demonstrated inhibition zones of 8.9 ± 1.1 mm (Bacillus subtilis), 12.6 ± 1.6 mm (Escherichia coli), 8.2 ± 1.2 mm (Fusarium oxysporum), and 9.2 ± 1.1 mm (Aspergillus niger). In silico analyses showed high absorption, favorable metabolism and excretion, and minimal toxicity, with no hERG channel inhibition or hepatotoxicity. The comprehensive results highlight the significant antioxidant, antidiabetic, and antimicrobial activities of S. marianum extract, suggesting its potential for therapeutic and preventive applications.

Computational and GC-MS screening of bioactive compounds from Thymus Vulgaris targeting mycolactone protein associated with Buruli ulcer

Buruli ulcer (BU) a neglected disease induced by the bacterium Mycobacterium ulcerans, predominantly impacts tropical and subtropical areas with its pathophysiology ascribed to the Mycolactone protein. Current antibiotics frequently prove insufficient to manage advanced or chronic ulcers and the rise of drug resistance presents a considerable challenge. This work aims to address these challenges by employing computational methods to identify therapeutic candidates from organic compounds, which may be developed into more effective therapies for Buruli ulcer. The Gas-Chromatography Mass Spectrometry (GCMS) analysis of the Thymus Vulgaris identified the 29 bioactive compounds as potential drug candidates having different medicinal properties. Out of the 29 compounds against the mycolactone protein, 14 compounds demonstrated a binding affinity higher than − 6 kcal/mol predicted through PyRx. Among all compounds, gamma sitosterol and borneol showed the highest binding affinity − 7.7 kcal/mol. The ADMET analysis predicted that the compound borneol crosses the PGP + through the Blood Brain Barrier and gastrointestinal tract without violating Lipinski’s rule of 5 having high water solubility, and log p-value of 2.29. The molecular dynamic simulation was performed and showed the Eigenvalue of 1.332692e-04. The leads identified in the study have demonstrated encouraging outcomes with regard to their efficacy, toxicity, pharmacokinetics, and safety. Further experimental investigations can be conducted to evaluate their anti-bacterial activity, and their molecular frameworks could be utilized as a valuable foundation for designing new drugs for the treatment of Buruli ulcer.

Novel rhodanine-thiazole hybrids as potential antidiabetic agents: a structure-based drug design approach.

New rhodanine-thiazole clubbed compounds (7a-7l) were synthesised and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro HPA, HLAG inhibition, and peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression assays. Through the biological study, compound 7f showed promising inhibitory activity against HPA with an IC50 value of 27.13 ± 1.02 μM and 7l exhibited better inhibition against HLAG with an IC50 value of 24.21 ± 1.12 μM. In addition, Lineweaver-Burk plot analysis suggested that 7l and 7f behaved as a mixed type of HLAG and HPA inhibitor and further, compound 7f showed significant PPAR-γ expression as compared to controls in a dose dependent manner; the expression can be attributed to its mapped pharmacophoric features with a phase screen score of 1.28 and vector score of 0.62. The proteins modulated by compounds include AMY2A, PPAR, and GAA proteins via MAPK, PPAR signalling pathways identified by cluster analysis and justified by molecular docking studies and MD trajectory analysis to evaluate the binding orientation and stability of the molecules, and the energy profiles of the molecules, both in complex with the protein, were assessed using MM/GBSA and DFT calculations, respectively. Finally, the pharmacokinetic profile was determined using ADMET analysis. Thus, from the above findings, it may demonstrate that rhodanine-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.

In-silico discovery of efficient second-generation drug derivatives with enhanced antihistamine potency and selectivity.

The current study focuses on the potential of second-generation antihistamines, which exhibit fewer side effects compared to first-generation drugs, to block the Histamine H1 receptor (H1R) and mitigate allergic responses. We screened several derivatives of second-generation drugs taking Desloratadine (Deslo) and Acrivastine (Acra) as seed compounds. We performed molecular docking, drug-likeness, quantum chemical calculations, UV-visible and infrared spectroscopy, molecular electrostatic potential (MEP) mapping for understanding drug derivatives potential as efficient drugs and molecular dynamics (MD). The results depicted that among all Deslo1 showed best binding energy of -8.6 kcal/mol and best inhibition constant too. Moreover, LEU157 formed a conventional hydrogen bond with a ligand at distance of 2.51 Å in Deslo1. Deslo2 showed 95.2 % intestinal absorption which is quite good. None of the drugs showed any toxicity. The residues from catalytic site like Phe 116, Leu 154 and Leu 157 showed reasonably small fluctuations owing to their interactions with respective ligands. The RMSDs of Acra1 and Deslo2 mostly stay within 1Å range. For MD simulations best docked compounds (Acra1, Acra2, Deslo1 and Deslo2) were chosen and carried for 120 ns (120 ×106 fs). MD simulations trajectory is analyzed for the assessment of some important parameters like RMSD, RMSF, SASA, and RG. Moreover, ADMET analysis are performed to confirm their drug-like properties. The molecular geometries of Acra2 are optimized in gas phase as well as water solvent environments to simulate aqueous like conditions for optimized geometries. Significant differences are observed in the bond lengths and angles especially for polar functional groups, due to the solvation of hydrogen-bond donors and acceptors. The current study identify new therapeutic candidates for managing allergic rhinitis, which may evoke the scientific interests of scientists through in-vivo testing of hit drugs that were not explored previously.

Molecular docking and molecular dynamics simulation studies of inhibitor candidates against Anopheles gambiae 3-hydroxykynurenine transaminase and implications on vector control.

Isoxazole and oxadiazole derivatives inhibiting 3-hydroxykynurenine transaminase (3HKT) are potential larvicidal candidates. This study aims to identify more suited potential inhibitors of Anopheles gambiae 3HKT (Ag3HKT) through molecular docking and molecular dynamics simulation. A total of 958 compounds were docked against Anopheles gambiae 3HKT (PDB ID: 2CH2) using Autodock vina and Autodock4. The top three identified hits were subjected to 300 ns molecular dynamics simulation using AMBER 18 and ADMET analysis using SWISSADME predictor and ADMETSAR. Replacement of alkyl attachment on C5 of isoxazole or oxadiazole derivative with a cycloalkyl group yielded compounds with lower binding energy than their straight chain counterparts. The top three compounds were brominated compounds, 2-[3-(4-bromophenyl)-1,2-oxazol-5-yl]cyclopentane-1-carboxylic acid, 2-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxylic acid, 3-[3-(4-bromo-2-methylphenyl)-1,2,4-oxadiazol-5-yl]cyclopentane-1-carboxylic acid, and they had binding energies of -8.58, -8.25, and -8.18kcal/mol in virtual screening against 2CH2 protein target, respectively. These compounds were predicted to be less toxic than temephos, a standard larvicide and more biodegradable than previously reported inhibitors. The three compounds exhibited a greater stabilizing effect on 2CH2 protein target than 4-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]butanoic acid, a previously reported inhibitor candidate with good larvicidal activity on Aedes aegypti. Further thermodynamic calculations revealed that the top three compounds possessed total binding energies (ΔGbind) of -26.64kcal/mol, -24.26kcal/mol and -14.11kcal/mol, respectively, as compared to -12.02kcal/mol for 4-[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]butanoic acid. These compounds could be better larvicides than previously reported isoxazole or oxadiazole derivatives and safer than temephos.