جستجوی مقالات مرتبط با کلیدواژه "admet" در نشریات گروه "شیمی"

Employing computer-aided drug design techniques, the physicochemical, biological, and pharmacokinetic properties of several derivatives of methyl α-D-mannopyranoside were explored. Geometrical optimization was conducted using density functional theory (DFT) with a 3-21G basis set, yielding crucial insights into the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). From these data, softness, electron affinity, ionization potential, electronegativity, hardness, electrophilicity, and chemical potential were derived. Notably, compound 1 (mannopyranoside) exhibited the widest energy gap (0.27439 eV), while compound 4 (lauryl derivatives) displayed the narrowest energy gap (0.01924 eV). Furthermore, comprehensive studies encompassing geometrical, thermodynamic, molecular orbital, and electrostatic potential analyses were conducted to elucidate the physical and chemical behavior of the compounds. Molecular docking against the Smallpox virus (PDB 3IGC) proteins enabled the investigation of binding affinity, mode, and interactions with the receptor. ADMET prediction was employed to compare the absorption, distribution, metabolism, and toxicity of the compounds, revealing that compound 6 (a palmitoyl derivative) has the highest free energy and internal energy. A 100 ns molecular dynamics (MD) simulation was used to observe the complex structure formed by the 3IGC protein under in silico physiological conditions to determine its stability over time. It showed a stable conformation and binding pattern in a stimulating mannopyranoside derivative environment. Overall, this study provides valuable insights into the biochemical impact of these compounds on the environment and the human body, offering significant implications for future research endeavors. These findings suggest promising prospects for the development of effective antiviral agents targeting smallpox.

Dual orexin receptor antagonists such as suvorexant, lemborexant, and daridorexant are the effective solutions for treating insomnia without inducing any dependency. In this study, we identified newer generation dual orexin receptor antagonist using receptor based pharmcophore modeling, virtual screening, molecular docking, MEP, FMO, and ADMET analyses. Two receptors such as 6TOT and 4S0V associated with human orexin1 and 2 were considered, respectively. Virtual screening process was performed using the pharmacophoric features of lemborexant and suvorexant using the Zinc database. Virtual screening helps to repurpose already established molecules in a Polypharmacological approach and also it reduces the burden of synthesis. Virtually screened molecules were docked to the active pocket of both receptors, and comparative analyses were performed. Once the reproducibility of binding energy scores and binding modes were validated, the top hit molecules with potential inhibitions against orexin 1 and 2 receptor were selected for further evaluations. MEP and FMO analyses of the best docked molecules were calculated by B3LYP functional and 6–311 G(d,p) levels using GAMESS software. Finally, ADMET analyses were also performed. ZINC84587472 and ZINC63746558 were the best docked molecules against orexin-1 and 2 receptors, respectively. Here, ZINC84587472 showed the highest levels of electronegativity and electrophilicity, respectively. ZINC84587472 was observed as the most reactive molecules. Computational studies confirmed that ZINC84587472 and ZINC63746558 molecules showed good orexin-1 and orexin-2 antagonists with good receptor binding and electronic properties.

Some ethyl 2-((1,2,3-oxadiazol-4-yl)thio)-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives (M1 to M20) were designed and developed as potential DPP-IV inhibitors. All the designed derivatives were subjected for binding affinity studies. Fortunately, 18 molecules displayed better binding affinity than native ligand (NL) present in the crystal structure of enzyme (PDB ID: 6B1E). From interactions of NL, it was observed that Glu206 and Arg358 are important amino acid residues to get good binding orientation. Fortunately, almost all the molecules developed at least one kind of interactions with either of these amino acids. Out of these, M17 was considered as most potent as it has developed 5 conventional-hydrogen bonds. To evaluate the stability of Compound M17 in complex with the DPP-IV enzyme, a 100 ns all-atom molecular dynamics (MD) simulation was conducted. The combination of hydrogen bonding, hydrophobic, ionic, and water-mediated interactions highlights the robust nature of the binding between Compound M17 and enzyme, ensuring the stability and efficacy of the complex throughout the simulation. From in silico screening, we have selected M3, M5, M12, M16, M17, and M18 for the synthesis. The synthesized compounds tested at 250 µM and all the compounds exhibited more than 90% of inhibition in in vitro enzyme assay. Compound M18 displayed 93.3±0.58% of inhibition and 13.14±0.49 µM of IC50 value which was highest amongst the synthesized compounds. It was concluded that, the synthesized compounds displayed optimum DPP-IV inhibitory activity, therefore these can be treated as lead nucleus for further development.

To tackle medication resistance in rheumatoid arthritis, type 1 diabetes, and Grave's disease, 32 compounds were chosen as new inhibitors of autoimmune disorders and underwent 2D-QSAR, 3D-QSAR, docking, ADMET, and molecular dynamics (MD) simulation experiments. Genetic approximation-multiple linear regression (GA-MLR) was used in the 2D-QSAR investigation. The experimental activities and those obtained by model 1 were shown to have a respectable connection (r2 = 0.7616 and q2 = 0.6327). The structure-activity relationships (SAR) were statistically studied using the 3D-QSAR technique, which produced strong statistical significance for one high predictive model, comparative molecular field analysis (CoMFA: Q2=0.785; R2=0.936; rext2= 0.818). The steric and electrostatic fields control the bioactivity, according to a thorough examination of the contour maps of the prediction models. This information is very useful in understanding the qualities that must be presented to create new and powerful inhibitors of autoimmune disorders. Through these discoveries, 70 new inhibitors with improved receptor-targeting activity were designed. The last lead compounds were compound 32 and designed compound D40, which were found by virtual screening and subsequent molecular docking. Compounds 32 and D40 have the ability to target proteins such as arginine deiminase 4 (PAD4), major histocompatibility complex (MHC) class II HLA-DQ-ALPHA chain, and thyrotropin receptor (or TSH receptor) proteins, according to the results of the MD simulation for each protein-ligand complex. Our studies suggest that compound 32 and designed compound D40 be studied in vitro and in vivo against some of the selected autoimmune disorders. The MM/GBSA binding free energies are also measured for the selected drugs. For pattern recognition, structural similarity, and hotspots binding energy prediction.

VEGFR-2 expression and its activation are upregulated, causing angiogenesis. This process is significant and critical for tumor development, progression, and metastasis. As a consequence, VEGFR-2 has become the center of attention for cancer treatment scientists because the inhibition of VEGFR-2 kinases has become essential in the field of oncological research with the ultimate goal of stopping angiogenesis and terminating the development of malignant tumors. In this study, the target molecule inhibitors were developed via the synthesis of Benzimidazole-1,3,4-thiadiazol-2-amine derivatives. Out of 30 screened molecules, AP3, AP5, AP10, AP12, AP16, AP17, AP18, AP20, AP24, and AP29 which possess most drug-likeness properties are considered as the most potent and either selected for wet lab synthesis. VEGFR-2 kinase assay was performed at a test concentration of 10 μM. Compounds AP17 and AP29 are at top of the list due to their excellent inhibition activities of the VEGFR2 kinase (IC50 values are 1.86 µM and 3.84 µM, respectively), and compared to pazopanib (the IC50 value is 0.092 µM), they displayed this activity quite well. The activity of the synthesized compounds were determined in 5 cancerous cell lines (breast-MCF-7, MDA-MB-231, kidney-HEK-293, and lung-A549) with sulforhodamine B (SRB) assay. Based on the trial, the compound AP17 displayed the best potency against A-549 with a GI50 value of 5.35 μM, more so than against HEK-293 and MCF-7 cells with a GI50 value of 7.20 and 8.90 μM, respectively. The fact that only this particular compound demonstrated medium cytotoxicity against the MDA-MB-231 (GI50 =18.89 μM) reflects the popularity and preference of this compound. As a consequence of the current examination, we have concluded that the inhibitors possess good potential of VEGFR2 kinase for future use.

This study presents a novel approach for discovering potent antioxidants from natural sources. We explored Polygonum salicifolium, a medicinal plant, using combined experimental and computational methods. The crude extract exhibited significant concentration-dependent free radical scavenging activity. GC-MS analysis revealed 33 components, with 5 exhibiting key bioactivity. DFT calculations suggest Hydrogen Atom Transfer (HAT) as the dominant mechanism for the 5 bioactive compounds under study, as compared to single electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). In addition, molecular docking simulations were conducted to assess the interaction of these compounds with the SOD2 receptor. The results indicated that compounds PS1, PS2, PS3, PS4, and PS5 exhibited re-rank scores of -82.9522, -81.4507, -71.1435, -82.9793, and -77.4562 kcal/mol, respectively, surpassing the reference antioxidant (Nebivolol = -63.9865 kcal/mol). The ADMET profiling indicated that all the studied compounds are generally safe for potential medicinal applications. These findings suggest that P. salicifolium extract is a promising natural source of antioxidants with potential applications in the treatment and prevention of oxidative stress-related diseases.

Plasmodium falciparum is the most virulent malaria-causing species and has become prevalent in developing countries. Due to the persistent resistance of malaria to standard drugs and the diverse side effects associated with their use, there is a need to research more effective alternatives. Thiazole hydrazines have emerged as promising candidates. In this study, molecular docking studies and density functional methods were used to predict molecular descriptors of each ligand. Likewise, the quantitative structural activity relationship (QSAR) model was built using a multiple linear regression (MLR) approach to predict the inhibitory concentration (IC50) of the ligands. One of the twelve thiazole hydrazines investigated in this work is 4-chloro-2-[(E)-[[4-(4-chlorophenyl)thiazol-2-yl]hydrazono]methyl]phenol (C10), which showed a binding affinity of -9.3 to Plasmodium falciparum thioredoxin reductase (PDB 4J56). The binding affinity of this thiazole derivative indicates better inhibition of Plasmodium falciparum thioredoxin reductase (PDB Code: 4J56) than quinine, a widely adopted anti-malaria drug. A comprehensive evaluation of more parameters including ADMET, bioactivity, oral bioavailability, and Prediction of Activity Spectra for Substances (PASS) of the twelve compounds validates 4-chloro-2-[(E)-[[4-(4-chlorophenyl)thiazol-2-yl]hydrazono]methyl]phenol as a potent photochemical capable of acting as a chemotherapeutic agent against Plasmodium falciparum.

In this work, molecular docking was performed to evaluate the anticancer activities of cannabidiol on various targeted proteins. Interactions and significant binding energy prove that cannabidiol can be synthesized and tested as a potent drug that treats all types of human cancer safely. The data obtained highlight the key amino acids involved in the ligand/protein interactions and show that the designed cannabidiol-bound complexes exhibited the best confirmation in the binding site. In addition, a DFT optimization of the geometry and orbital frontier analysis was performed to describe the chemical reactivity of the studied molecule. A pharmacokinetic and bioavailability study in the body was performed by ADMET proprietes. The results of the molecular docking indicate that cannabinol can tested as a potent drug to treat human cancer, given its interactions and significant binding energy up to -8,6 kcal/mol with FAAH protein.

This study investigates the stability, reactivity, and antiviral potential of novel 1,3,4-thiadiazole and1,3-thiazolidine-4-one derivatives using a combination of Density Functional Theory (DFT) calculationsand molecular docking. DFT analyses, including molecular electrostatic potential (MEP) mapping,reactivity indices (electronegativity, electrophilic index, softness, and hardness), and frontiermolecular orbitals (HOMO-LUMO), were conducted to understand the chemical properties of themain compound. PASS predictions indicated strong activity of these compounds as Mcl-1 antagonistsand antivirals. The docking studies, performed using AutoDock Vina v1.1.2 in PyRx 8, evaluated thebinding affi nities of 21 compounds against SARS-CoV-2 and rhinovirus, comparing them withstandard drugs (Lopinavir, Nafamostat, and Remdesivir). The compounds exhibited binding affi nitiesranging from -6.9 to -8.5 kcal/mol, suggesting notable antiviral activity. Additionally, ADMET analysis(absorption, distribution, metabolism, excretion, and toxicity) was carried out using ADMET-AI andadmetSAR 2.0, confi rming their drug-like properties and suitability for further medicinal chemistrydevelopment.

Given the pandemic of COVID-19, the new generation of coronavirus noted SARS-CoV-2 still remains a global health threat to this day, the absence of effective and reliable treatments against its severe acute respiratory syndromes implies day after day forced and relentless research in order to delimit the degree of danger of this virus. In this work, we performed in silico studies on some Eugenol derivatives in order to suggest promising molecules that could be anti- SARS-CoV-2 drugs, in a first step, a molecular docking study was conducted on a set of 59 compounds derived from Eugenol as inhibitors of the main protease SARS-CoV-2, based on the results, six compounds were distinguished by the best energy scores, have been chosen to show the binding mode of eugenol derivative inhibitors, subsequently, we proceeded to the prediction of pharmacokinetics and ADMET properties on six compounds that showed good affinity towards the main protease, only one compound, according to the selection criteria of Lipinski and Veber, showed pharmacological properties suitable for human administration. In addition, the binding stability of the selected compound with our base protein was evaluated by performing molecular dynamics simulations which consequently showed good stability with SARS-CoV-2 Mpro under aqueous conditions.

Despite advancements in analytics and therapy, breast cancer remains one of the leading causes of death and the second most prevalent cancer among women worldwide. This study focuses on the development of more potent and safer coumarin derivatives as anti-breast cancer agents. The design process involved molecular docking studies and structural modifications based on a design template. The docking studies involved 26 coumarin derivatives and the active site residues of VEGFR-2 target protein. Among the compounds tested, compound 7 demonstrated a higher docking score (-149.893 kcal/mol) compared to Sorafenib (-144.289 kcal/mol), which served as the design template. By introducing electron-rich -NH2 and -OH groups to the various positions on the template, resulting in increased electron density and basic character, five novel derivatives with improved binding affinities (-156.185 to -171.985 kcal/mol) were designed. Consequently, these compounds exhibit enhanced binding capabilities compared to Sorafenib. Moreover, pharmacological studies indicate that the designed derivatives possess drug-like qualities and favorable ADMET profiles. As a result, these research findings hold promise for the discovery of new and improved drugs for the treatment of breast cancer.

In this work, a number of 2-acetylphenol-rivastigmine hybrids have been rationally created as drugs for the treatment of behavioral disorders, especially depression. On a series of inhibitors that are 2-acetylphenol-rivastigmine hybrids, we have used virtual in silico screening techniques such as Three-dimensional QSAR, molecular docking, and pharmacokinetic properties (absorption, distribution, metabolism, excretion, and toxicity (ADMET) techniques. The aim of this study was to obtain new ligands with high inhibitory activities. The best 3D-QSAR model was created using the PLS approach and comparative molecular similarity index analysis (CoMSIA), which demonstrated strong correlative and predictive capabilities (r2 = 0.904, q2 = 0.699 and SEE = 0.094). The change of biological activity with four main components is significantly influenced by the steric, electrostatic, hydrophobic, and H-bond acceptor fields. Using these acceptable results, new molecules were developed and analyzed using in silico drug similarity, ADMET and molecular docking.

The appearance of severe acute respiratory syndrome coronavirus 2 (COVID-19) is at its peak; with the growing number of people infected with COVID-19, there is an urgent need to find effective treatments for this outbreak. The current situation appears to call for drug repurposing. In our hunt for a viable medication against this virus, we used an in-silico strategy to test four conventional medicines, including Ritonavir and Hydroxychloroquine, against the spike glycoprotein of COVID-19. A docking simulation was performed to assess the drug's binding affinity. We discovered a single medication compound 36 against SARS-coronavirus spike glycoprotein. The compound was found to have a strong binding affinity against the target protein. The chemical was discovered to have a high affinity for the target protein. Furthermore, no conventional medicines efficiently bonded to the SARS-coronavirus spike glycoprotein. The current investigation concluded that the compound 36 is a highly stable anti-SARS-coronavirus spike glycoprotein medication. Furthermore, none of the standard drugs had a high affinity for the SARS-coronavirus spike glycoprotein binding site.

Typhoid fever, a disease caused by a Gram-negative bacterium known as Salmonella typhi constitutes a significant cause of morbidity and mortality, especially in developing nations. The rising cases of resistance to existing antibiotics by this bacterium have necessitated the search for the novel drug candidates. In this study, a data set of some anti-Salmonella typhi pyridine-substituted coumarins were subjected to Molecular Docking-based Virtual Screening against the active sites of DNA gyrase of the bacterium using EasyDock Vina 2.0 of AutoDock Vina software. Prior to the molecular docking calculation, the structures of the compounds were optimized using the DFT method of Spartan 14 software to obtain their minimum energy conformations. The outcome of the Virtual Screening led to the selection of compounds 12, 13, and 15 as template molecules for the design of more potent analogues because they bind better to the active sites of DNA gyrase target with binding affinity values (ΔG) of -9.6 kcal/mol, -9.5 kcal/mol and -9.6 kcal/mol, respectively. Subsequently, the template molecules were subjected to structural modifications leading to the design of more potent analogues with ΔG values ranging from -9.9 kcal/mol to -10.6 kcal/mol against DNA gyrase target. Furthermore, insilico drug-likeness and ADMET evaluation of the designed ligands revealed that they possess good oral bioavailability and positive pharmacokinetic profiles. It is hoped that the findings of this research would provide an excellent template for the development of novel drugs that could curb the alarming rate of resistance to existing antibiotics by Salmonella typhi.

V600E-BRAF mutation has been detected in several malignant tumours. Developing potent V600E-BRAF inhibitors is considered an essential step in curing diverse cancer types. In this work, computational techniques such as the molecular docking simulation, ADMET evaluation, and density functional theory (DFT) calculations were applied to screen and identify the most potential V600E-BRAF  inhibitors from a series of 39 previously synthesized novel pyrrolo[2,3-b]pyridine derivatives. Five top-ranked compounds (3, 18, 32, 33, and 35) with remarkable docking scores, compared to Vemurafenib (FDA-approved V600E-BRAF inhibitor), were selected. The formation of H-bonds and hydrophobic interactions with critical residues for V600E-BRAF as Vemurafenib confirmed the high stability of these complexes. Subsequently, the compounds were screened by analyzing their drug-likeness and ADMET properties. The compounds possess safety agents and effective combination therapy as pharmaceutical drugs. The highest occupied molecular (HOMO) orbital, lowest unoccupied molecular orbital (LUMO), and energy gap values were calculated using the DFT. The molecular electrostatic potential (MEP) was analyzed to illustrate the charge density distributions that could be associated with the biological activity. Therefore, compound 35 emerged as a potential hit with enhanced pharmacological properties and could be presented as a promising cancer drug candidate.

Obesity, a lipid metabolic disorder characterized by excess fat deposition in the adipose tissue, is among the leading top global health challenges. The only Food and Drug Agency (FDA) approved drug (Orlistat®) for its treatment has shown some adverse effects. To find new compounds that may be more effective or with less adverse effects compared to Orlistat®. Catechin and chlorogenic acid were computationally studied using molecular docking and validated with molecular dynamics simulation techniques. The ADMET and drug-likeliness evaluation of the two compounds was carried out in silico. The binding affinities, structural stability, and flexibility vis-a-vis root-mean-square deviation (RMSD) and root-mean-square fluctuations (RMSF) plots, hydrogen bonding, and surface area analysis of the two compounds were compared to the Orlistat®. It was found that the selected two compounds passed Lipinski’s rule of 5 and other parameters expected of a drug. In addition, both catechin and chlorogenic acid exhibited good docking scores, better fit and molecular interactions, good structural stability, and flexibility compared to Orlistat®.

The SARS-CoV-2 is the novel coronavirus that causes the pandemic COVID-19, which has originated in Wuhan, China, in December 2019. Early studies have generally shown that human Angiotensin-Converting Enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) are responsible for the viral entry of SARS-CoV-2 into target cells. TMPRSS2 as androgen-regulated is highly expressed in the prostate and other tissues including the lung. We investigated the interaction between the TMPRSS2 protein and selected antiandrogens, namely Bicalutamide, Enzalutamide, Apalutamide, Flutamide, Nilutamide, and Darolutamide using in-silico molecular docking. The results showed that Apalutamide (-8.8 Kcal/mol) and Bicalutamide (-8.6 Kcal/mol) had the highest docking score. The molecular docking process was validated by re-docking the peptide like-inhibitor-serine protease hepsin and superimposing them onto the reference complex. Last of all, the tested compounds have been evaluated for their pharmacokinetic and drug likeness properties and concluded that these compounds except Nilutamide (mutagenic) can be granted as potential inhibitors of SARS-CoV-2. This in-silico study result encourages its use as means for drug discovery of new COVID-19 treatment.

Recently, a new series of N-benzyl-3,6-dimethylbenzo[d]-isoxazol-5-amine derivatives and its prostate anti-cancer activity were produced and evaluated, respectively. Its compounds were perceived to have a strong inhibitory effect on the bromodomain of the related Tripartite motif-containing protein 24 (TRIM24). The 3D-QSAR study was applied utilizing the methods of Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). This gave result to the cross-validation coefficient (Q2) values of 0.850 and 0.92, the determination coefficient (R2) values of 0.998 and 0.987, respectively. The predictive capacity of these models is based on a test set of seven molecules that generated acceptable values of coefficient of determination (R2 test) of 0.793 and 0.804, corresponding respectively to CoMFA and CoMSIA., respectively. The study used molecular docking analysis to validate 3D-QSAR methods and to explain the binding site interactions and energy between the TRIM24 bromodomain receptor and the most active ligands. Based on the results of the previous model, it was allowed for us to predict new and active compounds and its pharmacokinetic properties were verified using drug-likeness and ADMET prediction. Finally, to affirm the dynamic stability and behavior of the molecules, the most appropriate docked candidate molecules were simulated by molecular dynamics

This study aimed at designing highly potent dengue virus (DENV) inhibitors targeting the NS2B-NS3 protease from 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole (BTZO) hybrid through quantitative-structure-activity relationship (QSAR) and subsequently structure-based design, molecular docking, and ADMET (Adsorption-Distribution-Metabolism-Excretion Toxicity) of the designed BTZO derivatives. A QSAR model was developed to correlate the biological activity with the descriptor calculated from the BTZO hybrid using multiple linear regression. The model was validated and the information from the model was used to design more potent derivatives which were evaluated through molecular docking and ADMET prediction. The QSAR model showed good statistical quality (R2Training = 0.89228, R2predicted = 0.72734 R2adjusted = 0.87074, Q2LOO = 0.81896, and cR2p = 0.8154) leading to the design of nine active BTZO derivatives with better inhibitory activity than the lead compound (7n). A binding score of -23.731, -20.210, -23.568 kcal/mol better than Panduratin and Ribavirin (-14.1715, -17.2571 kcal/mol) for compounds C-148, C-205, and C-206 respectively were obtained, including good ADMET properties. This discovery not only aided in understanding the binding manner of BTZO hybrid to the NS2B-N3 targets but also provided information for the development of active NS2B-N3 protease inhibitors.

3D-QSAR has indeed established itself as a very useful component in the design of compounds with biological potential. The use of this tool will therefore make it possible to more easily target the modulations to be carried out in order to improve the inhibitory capacity of the series studied.Statistical analyses of CoMFA and CoMSIA molecular interaction field descriptors and the model validation methods they generate are presented and applied to the three-dimensional quantitative structure-activity relationships study of a series of 32 wild-type HCT 116 p53 inhibitor styrylquinolines. The selected CoMFA and CoMSIA models were generated by the partial least squares "PLS" method and all had very good internal prediction and cross-validation coefficient values Q² of 0.601 and 0.6 respectively. In view of the results obtained by the contour maps of the developed models as well as the results of molecular docking, new analogues of styrylquinoline were designed.The study of the physicochemical, pharmacokinetic and potential toxicity properties shows that the two newly predicted compounds T1 and T3 presented a better ADMET profile, in particular a good gastrointestinal absorption, compared to the most active compound taken from the literature,