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Our research is dedicated to combating HIV by targeting its Matrix (MA) domain, which is crucial for viral assembly and replication. This strategy specifically aims to interrupt early-stage infection and deter drug resistance by focusing on this essential domain. Due to the MA domain's conservation across different HIV strains, our approach promises broad-spectrum efficacy, which is particularly crucial in regions marked by significant genetic diversity and resistance issues. In our study, we introduce CNP0269688, a natural product that exhibits high affinity for the HIV-1 Matrix. Through detailed molecular dynamics simulations, we have assessed the compound's structural stability and interaction dynamics, particularly its potential to hinder Protein-tRNA interactions. This analysis lays the groundwork for future experimental investigations. Our efforts are steps toward enhancing HIV treatment, reducing viral transmission, and curbing drug resistance, with the ultimate aim of controlling and eradicating the pandemic, thereby contributing significantly to public health and scientific advancement.

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Mitragyna speciosa is famous for its addictive effect. On the other hand, this plant has good potential as an antioxidant agent, and so far, it was not explicitly explained what the most contributing compound in the leaves to that activity is. This study has been conducted using several computational methods to determine which compounds are the most active in interacting with cytochrome P450, myeloperoxidase, and NADPH oxidase proteins. First, virtual screening was carried out based on molecular docking, followed by profiling the properties of adsorption, distribution, metabolism, excretion, and toxicity (ADMET); the second one is the molecular dynamics (MD) simulations for 100 ns. The virtual screening results showed that three compounds acted as inhibitors for each protein: (-)-epicatechin, sitogluside, and corynoxeine. The ADMET profiles of the three compounds exhibit good drug ability and toxicity. The trajectories study from MD simulations predicts that the complexes of these three compounds with their respective target proteins are stable. Furthermore, these compounds identified in this computational study can be a potential guide for future experiments aimed at assessing the antioxidant properties through in vitro testing.

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Investigation into the interactions between photoprotective agents and skin can offer a precise understanding of their biological behaviors in vitro and in vivo, providing crucial insights for generating new substances. For this purpose, we designed and synthesized a series of naphthoxazine derivatives and examined their photoprotective properties. 1,3-naphthoxazine derivatives were synthesized through the multi-component reaction of 2-naphthol, arylamines and aromatic aldehydes in the presence of copper(II) trifluoromethanesulfonate (Cu(OTf)2) and (±)-Camphor-10-sulfonic acid ((±)-CSA) catalyst system under sonication. The potential of these synthesized 1,3-naphthoxazine derivatives as antioxidants and viable organic structural-based sunscreen ingredients has been investigated. Sun protection factor (SPF) assay results showed that especially compounds 4i, 4c, 4k, 4d, 4r, and 4h had remarkably high activity (23.65, 23.57, 23.04, 21.94, 20.80, and 20.26, respectively at 900 µg/mL concentration). Additionally, antioxidant activity of the synthesized compounds was evaluated and compounds 4h, 4e, 4b, and 4j exhibited the highest activities in DPPH scavenging activity assay (86.46 %, 82.83 %, 80.78 %, and 80.65 % respectively at 400 µg/mL concentration). The synthesized compounds exhibit promising characteristics for effective UV radiation absorption, suggesting their suitability for inclusion in sunscreen formulations. Cytotoxic activity of compound 4k against normal human fibroblast cell line (MRC-5) was determined by CVDK-8 method. The results revealed that the compound provided remarkable viability (87.55 %) of MRC-5 cells at concentration of 100 µM. The study explores their efficacy in providing broad-spectrum protection against UVA and UVB rays, degradation and photostability, ADMET profile, and other pharmacokinetic properties.

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Background: Despite the widely reported potentials of n-Hexadecanoic acid (HA) as a bioactive, its multi-stage antiplasmodial activity and toxicity profiles remain largely unknown. Methodology: Thus, this study uses a combination of in silico approaches and in vivo studies to assess the inhibitory activities of HA at different stages of the Plasmodium lifecycle, antiplasmodial performance, and toxicity profiles. The HA was retrieved from the PubChem database, while antiplasmodial target proteins from different stages of the Plasmodium falciparum life cycle were collated from the Protein Databank (PDB). Molecular Docking and Visualization were conducted between the compound and target proteins using AutoVina PyRx software and Biovia Discovery Studio, respectively. Also, the AdmetLab 3.0 algorithm was used to predict the absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of HA. Based on a 4-day suppressive test, the antiplasmodial activity against the Plasmodium berghei ANKA strain in mice was evaluated. Furthermore, subacute toxicity and micronucleus assays were used for further toxicity assessment. Results: The molecular docking analysis indicates multi-stage, multi-target potentials of HA with favourable ligand-receptor complexes across the four Plasmodium falciparum stages. Meanwhile, the mice administered with 100 mg/kg, 50 mg/kg, and 10 mg/kg of HA demonstrated considerable chemosuppression in a dose-dependent manner of 89.74%, 83.80%, and 71.58% percentage chemosuppression, respectively, at p < 0.05. The ADMET prediction, histopathological tests, and micronucleus assays show that HA is safer at a lower dose. Conclusion: This study showed that n-Hexadecanoic acid is a potential drug candidate for malaria. Hence, it is recommended for further molecular and biochemical investigations.

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Seaweed endophytes are a rich source of microbial diversity and bioactive compounds. This review provides a comprehensive analysis of the microbial diversity associated with seaweeds and their interaction between them. These diverse bacteria and fungi have distinct metabolic pathways, which result in the synthesis of bioactive compounds with potential applications in a variety of health fields. We examine many types of seaweed-associated microorganisms, their bioactive metabolites, and their potential role in cancer treatment using a comprehensive literature review. By incorporating recent findings, we hope to highlight the importance of seaweed endophytes as a prospective source of novel anticancer drugs and promote additional studies in this area. We also investigate the pharmacokinetic and pharmacodynamic profiles of these bioactive compounds because understanding their absorption, distribution, metabolism, excretion (ADMET), and toxicity profiles is critical for developing bioactive compounds with anticancer potential into effective cancer drugs. This knowledge ensures the safety and efficacy of proposed medications prior to clinical trials. This study not only provides promise for novel and more effective treatments for cancer with fewer side effects, but it also emphasizes the necessity of sustainable harvesting procedures and ethical considerations for protecting the delicate marine ecology during bioprospecting activities.

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INTRODUCTION: Aspergillus fumigatus, a significant fungal pathogen, poses a threat to human health, especially in immunocompromised individuals. Addressing the need for novel antifungal strategies, this study employs virtual screening to identify potential inhibitors of Fructosamine oxidase, also known as Amadoriase II, a crucial enzyme in A. fumigatus (PDB ID: 3DJE). METHOD: Virtual screening of 81,197 triazole derivatives was subjected to computational analysis, aiming to pinpoint molecules with high binding affinity to the active site of Fructosamine oxidase. Subsequently, an in-depth ADMET analysis assessed the pharmacokinetic properties of lead compounds, ensuring their viability for further development. Molecular dynamics simulations were performed to evaluate the stability of top-ranked compounds over time. RESULTS: The results unveil a subset of triazole derivatives displaying promising interactions, suggesting their potential as inhibitors for further investigation. CONCLUSION: This approach contributes to the development of targeted antifungal agents, offering a rational starting point for experimental validation and drug development against Aspergillus fumigatus infections.

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BACKGROUND: Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities. OBJECTIVE: To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA. METHODS: The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties. RESULTS: Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1 ) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability. CONCLUSION: Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

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Vitiligo is a prevalent autoimmune disease affecting the quality of life and self-confidence. Total 25 phytochemicals from plants were screened by using four target proteins involved in the pathogenesis of vitiligo. The binding affinity of the ligands ranged between -10.3 and -4.5 kcal/mol. The top 10 phytochemicals i.e. rosmarinic acid, piperine, tamarixetin, desmethoxycurcumin, bisdemethoxycurcumin, isorhamnetin, quercetin, vicenin II, genkwanin, and aloe-emodin showed good inhibition with binding affinity ranged from -10.3 to 9.4 Kcal. The ADMET profiling revealed that these phytochemicals might be safe for the treatment of vitiligo. In MD simulation, rosmarinic acid, piperine, and tamarixetin with MAO-A formed stable complexes and the free binding energies of the complexes were -34.02 ± 6.94, -33.51 ± 2.65, and -27.17 ± 3.28. Furthermore, the ligands formed hydrogen bonds with targets, suggested that rosmarinic acid, piperine, and tamarixetin have potential to serve as lead compounds for developing novel therapeutics for vitiligo after in vitro and in vivo studies.

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Objective: Biological studies have elucidated that phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the serine synthesis pathway in humans that is abnormally expressed in numerous cancers. Inhibition of the PHGDH activity is thought to be an attractive approach for novel anti-cancer therapy. The development of structurally diverse novel PHGDH inhibitors with high efficiency and low toxicity is a promising drug discovery strategy. Methods: A ligand-based 3D-QSAR pharmacophore model was developed using the HypoGen algorithm methodology of Discovery Studio. The selected pharmacophore model was further validated by test set validation, cost analysis, and Fischer randomization validation and was then used as a 3D query to screen compound libraries with various chemical scaffolds. The estimated activity, drug-likeness, molecular docking, growing scaffold, and molecular dynamics simulation processes were applied in combination to reduce the number of virtual hits. Results: The potential candidates against PHGDH were screened based on estimated activity, docking scores, predictive absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, and molecular dynamics simulation. Conclusion: Finally, an all-in-one combination was employed successfully to design and develop three potential anti-cancer candidates.

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In the twenty-first century, we are experiencing persistent waves of diverse pathogen variations, contributing significantly to global illness and death rates. Within this varied spectrum of illnesses, malaria and oxidative damage emerge as prominent obstacles that have persistently affected human health. The motivation for exploring the antioxidant potential of transition metal (II) complexes with tridentate Schiff base ligands is driven by the need for effective treatments against malaria and oxidative stress-related conditions. Both malaria and oxidative damage are significant global health concerns. Transition metal complexes can potentially offer enhanced anti-malarial and antioxidant activities, providing a dual benefit. To explore the aforementioned facts and examine the therapeutic potential, the previously synthesized pyrrolopyrimidinehydrazide-3-chlorobenzaldehyde, such as HPPHmCB ligand(1)andtheirMn(II),Fe(II),Co(II),Ni(II), Pd(II),Cu(II),Zn(II),Cd(II),Hg(II)complexes(2-10) of benzaldehydes and pyrrolopyrimidinehydrazide were proposed for in vitro anti-malarial and antioxidant investigation. These compounds were assessed for their anti-malarial efficacy against Plasmodium falciparum using a micro assay protocol, with IC50 values indicating the concentration required to inhibit parasite maturation by 50%. The Hg(II) complex displays pronounced antimalarial activity with an IC50 value of 1.98 ± 0.08 µM, closely aligning with the efficacy of quinine, whereas Zn(II), Cu(II), Pd(II) complexes demonstrates most significant anti-malarial activity, with IC50 values close to the reference compound quinine. The antioxidant activity of the compounds was evaluated using the DPPH assay, with several metal complexes such as Cu(II)and Zn(II) showing strong potential in neutralizing oxidative stress. Furthermore, molecular docking simulations were conducted to explore the binding interactions of the compounds with PfNDH2, providing insights into their pharmacological potential. The study also examined the electronic properties, solubility, and potential hepatotoxicity of the compounds. The findings suggest that the metal complexes could be promising candidates for further development as anti-malarial agents, offering enhanced potency compared to the base compound.

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Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a phytochemical compound that is commonly found in conjugated forms within mono-, di-, polysaccharides and other organic compounds in cell walls of grain, fruits, and vegetables. This compound is highly abundant in the palm oil waste. The aim of the study was to predict the anticancer activity of ferulic acid against the breast cancer cell lines (MCF-7) receptors through a computational analysis. MCF-7 receptors with PDB IDs of 1R5K, 2IOG, 4IV2, 4IW6, 5DUE, 5T92, and 5U2B were selected based on the Simplified Molecular Input Line Entry System (SMILES) similarity of the native ligand. Thereafter, the protein was prepared on Chimera 1.16 and docked with ferulic acid on Autodock Vina 1.2.5. The ligand-protein complex interaction was validated by computing the root mean square fluctuation (RMSF) and radius of gyration (Rg) through molecular dynamic simulation. In addition, an absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was performed on ferulic acid using the pkCSM platform. The molecular docking revealed that the ferulic acid could interact with all receptors as indicated by the affinity energy <-5 kcal/mol. The compound had the most optimum interaction with receptor 2IOG (affinity energy=-6.96 kcal/mol), involving hydrophobic interaction (n=12) and polar hydrogen interaction (n=4). The molecular dynamic simulation revealed that the complex had an RMSF of 1.713 Å with a fluctuation of Rg value around 1.000 Å. The ADMET properties of ferulic acid suggested that the compound is an ideal drug candidate. In conclusion, this study suggested that ferulic acid, which can be isolated from palm oil waste, has the potential to interact with MCF-7 receptors.

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Postprandial hyperglycemia (PPG) exacerbates endothelial dysfunction and impairs vascular function in diabetes as well in healthy people. Though synthetic drugs are available to regulate PPG, the severe gastrointestinal side effects of those medications have prompted the search for alternative treatments. Recently, some phytochemicals captured the attention because of their inhibitory effects on α-amylase to control diabetes. The aim of this study was to investigate and identify potential alpha-amylase inhibitors in C. indica and W. coagulans. This study also aims to understand one of the possible mechanisms of action of plants for their anti-diabetic activity. A total of 36 phytochemical ligands were subjected for protein-ligand docking analysis. Among the phytochemicals, Taraxerol and Epoxywithanolide-I demonstrated significant binding free energy of - 10.2 kcal/mol and - 11.9 kcal/mol respectively, which was higher than the reference acarbose with - 8.6 kcal/mol. These molecules were subjected for molecular dynamics simulation (MDS) analysis with alpha-amylase protein for a duration of 150 ns. Among the three complexes, Taraxerol and Epoxywithanolide-I complexes demonstrates strong potential as inhibitors of the target protein. MDS results were analyzed via root mean square deviation (RMSD), fluctuation of residues, potential energy, radii of gyration and solvent access surface area analysis. Taraxerol demonstrated a significantly low potential energy of - 1,924,605.25 kJ/mol, and Epoxywithanolide-I demonstrated - 1,964,113.3 kJ/mol of potential energy. RMSD plot shows that Epoxywithanolide-I has much higher stability than the other MDS complexes. Drugability and toxicity studies show that the test ligands are demonstrating strong potential as drug like molecules. The results of the study conclude that, Taraxerol of C. indica and Epoxywithanolide-I of W. coagulans are strong inhibitors of alpha-amylase enzyme and that, this is one of the possible mechanisms of action of the plants for their reported anti-diabetic activities. Further in-vitro analysis is in demand to prove the observed results.

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As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11's potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.

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Mutations in glucokinase (GCK) can either enhance or inhibit insulin secretion, leading to different forms of diabetes, including gestational diabetes. While many glucokinase activators (GKAs) have been explored as treatments, their long-term effectiveness has often been unsatisfactory. However, recent interest has surged with the introduction of dorzagliatin and TTP399. This study investigates the efficacy of four previously studied compounds (Swertiamarin, Apigenin, Mangiferin, and Tatanan A) in activating GCK using computational methods. Initial molecular docking revealed binding affinities ranging from -6.7 to -8.6 kcal/mol. The compounds were then evaluated for drug-likeness and pharmacokinetic properties. Re-docking studies were performed for validation. Based on their favorable binding affinities and compliance with Lipinski's rule and ADMET criteria, three compounds (Swertiamarin, Apigenin, and Tatanan A) were selected for molecular dynamics (MD) simulations. MD simulations demonstrated that Swertiamarin showed excellent stability, as indicated by analyses of RMSD, RMSF, radius of gyration (Rg), hydrogen bonding, and principal component analysis (PCA). These results suggest that Swertiamarin holds promise for further investigation in in vivo and clinical settings to evaluate its potential in enhancing GCK activity and treating diabetes. This study assessed the potential of four compounds as GCK activators using molecular docking, pharmacokinetic profiling, and MD simulations. Swertiamarin, in particular, showed significant stability and adherence to drug-likeness criteria, making it a promising candidate for further research in combating diabetes.

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The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family, a non-segmented negative-strand RNA virus. This article represents the computer-aided drug design (CADD) approach for identifying drug-like compounds that prevent the MARV virus disease by inhibiting nucleoprotein, which is responsible for their replication. This study used a wide range of in silico drug design techniques to identify potential drugs. Out of 368 natural compounds, 202 compounds passed ADMET, and molecular docking identified the top two molecules (CID: 1804018 and 5280520) with a high binding affinity of -6.77 and -6.672 kcal/mol, respectively. Both compounds showed interactions with the common amino acid residues SER_216, ARG_215, TYR_135, CYS_195, and ILE_108, which indicates that lead compounds and control ligands interact in the common active site/catalytic site of the protein. The negative binding free energies of CID: 1804018 and 5280520 were -66.01 and -31.29 kcal/mol, respectively. Two lead compounds were re-evaluated using MD modeling techniques, which confirmed CID: 1804018 as the most stable when complexed with the target protein. PC3 of the (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) was 8.74 %, whereas PC3 of the 2'-Hydroxydaidzein (CID: 5280520) was 11.25 %. In this study, (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) unveiled the significant stability of the proteins' binding site in ADMET, Molecular docking, MM-GBSA and MD simulation analysis studies, which also showed a high negative binding free energy value, confirming as the best drug candidate which is found in Angelica archangelica which may potentially inhibit the replication of MARV nucleoprotein.

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The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-ß3-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01-P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-ß3-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-ß3-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations.

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Objectives: Oxidative stress is implicated in several metabolic cascades involved in glucose control. Hence, investigating antioxidant and antidiabetic activities is crucial for discovering an effective diabetes mellitus (DM) agent. This study was aimed at probing the therapeutic efficacy of hydro-ethanolic extract of Combretum paniculatum (HECP) and gas chromatography-flame ionization detector (GC-FID)-identified phytochemicals as novel agents for DM. Methods: We determined the total phenols, flavonoids, and antioxidant vitamins in HECP using standard methods. A GC-FID was used to decipher phytochemicals of HECP. The antioxidant and antidiabetic activities of HECP were assessed using in vitro and in silico approaches. Results: The results revealed that HECP is affluent in phenols, flavonoids, and vitamin E and demonstrated engaging antioxidant activities in 1,1-diphenyl-2-picryl-hydroxyl (DPPH; IC50 = 0.83 µg/mL), thiobarbituric acid-reactive substances TBARS; IC50 = 2.28 µg/mL), and ferric-reducing antioxidant power assay (FRAP; IC50 = 2.89 µg/mL). Compared with the reference drug, acarbose, HECP exhibited good α-amylase and α-glucosidase inhibitory capacity, having IC50 values of 14.21 and 13.23 µg/mL, respectively, against 13.06 and 11.71 µg/mL recorded for acarbose. More so, the extract's top 6 scoring phytochemicals (rutin, kaempferol, epicatechin, ephedrine, naringenin, and resveratrol) had strong interactions with amino acid residues within and around α-amylase and α-glucosidase active site domains. All the compounds but rutin had favourable drug-like characteristics, pharmacokinetics, and safety profiles when compared with acarbose. Conclusion: Altogether, our results vindicate the use of this herb in treating DM locally and reveal that it has pharmaceutically active components that could be used as novel leads in the development of DM drugs.

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In the present work, we describe the synthesis of new 1,3,4-thiadiazole derivatives from natural (R)-carvone in three steps including, dichloro-cyclopropanation, a condensation with thiosemicarbazide and then a 1,3-dipolar cycloaddition reaction with various nitrilimines. the targeted compounds were structurally identified by 1H & 13C NMR and HRMS analyses. The cytotoxic assay demonstrated that some synthesized novel compounds were potent on certain cancer cell lines. Molecular modeling studies were undertaken to rationalize the wet lab study results. Furthermore, molecular docking was performed to unveil the binding potential of the most active derivatives, 3a and 6c, to caspase-3 and COX-2. The stabilities of the protein-compound complexes obtained from the docking were evaluated using MD simulation. Furthermore, FMO and related parameters of the active compounds and their stereoisomers were examined through DFT studies. The docking study showed compound 6c had a higher binding potential than caspase-3. However, the binding strength of 6c was found to be less than that of the standard drug, doxorubicin, as it formed lower conventional hydrogen bonds. On the other hand, compound 3a had a higher binding potential to COX-2. However, the binding potential 3a was much lower than that of the standard COX-2 inhibitor, celecoxib. The MD simulation demonstrated that the caspase-3-6c complex was less stable than the caspase-3-doxorubicin complex. In contrast, the COX-2-3a complex was stable, and 3a was anticipated to remain inside the protein's binding pocket. The DFT study showed that 3a had higher chemical stability than 6c. The electron exchange capacity, chemical stability, and molecular orbital distributions of the stereoisomers of the active compounds were also found to be alike.

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INTRODUCTION: The drug discovery and development domain has witnessed remarkable advancements due to the integration of computational methods, particularly Computer-Aided Drug Design (CADD). Discovering and creating new drugs involves structural modifications to enhance their effectiveness and physical attributes. This frequently includes employing semisynthetic techniques to investigate structure-activity relationships thoroughly. Noticeable progress in molecular biology, computational chemistry, combinatorial chemistry, and highthroughput screening is steering transformative changes in the pharmaceutical industry. BACKGROUND: High blood pressure or hypertension, a significant health issue, elevates the chances of heart, kidney, and brain complications, among other health concerns. It's a leading cause of untimely mortality globally. Therefore, it is important to search for new antihypertensive compounds that have fewer side effects and higher therapeutic activity. METHODS: Following molecular docking of the pyridazine derivatives, compounds were subjected to In-silico ADMET analysis. Subsequently, a low molecular weight compound was synthesized. Among the synthesized compounds characterization procedures include TLC, FT-IR, 1HNMR, and LC-MS techniques. RESULT: Compound 8 exhibited the most favorable molecular docking results with alpha A1 and beta 1 adrenergic receptors. Compounds 3, 5, and 6 fulfilled the essential ADMET criteria. Subsequently, Compounds 3, 4, and 5 underwent additional synthesis and characterization procedures, including TLC, FT-IR, 1H-NMR, and LC-MS techniques. CONCLUSION: Similar behavior was observed in compounds 6, 8, 10, and 11, all violating Pfizer's 3/75 rules in terms of TPAS. Hydrazinolysis of these b-benzoyl propionic acids produced pyridazine, which was utilized in synthesizing pyridazine derivatives. TLC, FT-IR, 1HNMR, and LCMS have characterized the compounds.

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Recent studies suggest that immunological and inflammatory responses in cardiovascular disorders, such as hypertension, myocardial infarction, ischemia injury, heart failure, arrhythmias, and atherosclerosis, may be affected by changes in the adenosine system. Pharmacological modulation of adenosine occurs through its receptor subtypes. In numerous preclinical studies, the activation of adenosine receptor 2A (A2AR) or the blockade of adenosine receptor 2B (A2BR) has shown promising results against cardiovascular diseases. This in silico study aimed to identify potential natural compounds that can activate A2AR or block A2BR without causing toxicity. Natural compounds were screened using COlleCtion of Open Natural ProdUcTs (COCONUT) or Natural Product Activity and Species Source Database (NPASS) databases to find agonists for A2AR or an antagonists/inverse agonists for A2BR. These compounds were then pre-filtered based on their toxicity profiles. The remaining compounds were subjected to molecular docking against A2AR and A2BR followed by molecular dynamics simulations were conducted. Finally, selected compounds' ADMET properties were determined using ADMETlab 2.0 web tool. Ultimately, one novel natural compound with potential agonistic activity (COCONUT IDs: CNP0450901) for A2AR and one antagonist/inverse agonist (rauwolscine) for A2BR were identified.