ADMET Analysis Research Articles

Molecular Docking and ADMET Analysis Strategy-Based Stability Indicating RP-HPLC-PDA Method Development and Validation of Toremifene.

The purpose of this research is to develop an analytical method and validate it according to ICH guidelines for the estimation of Toremifene by RP-HPLC-PDA with molecular docking and ADMET analysis. From molecular docking, it came to know the receptor affinity specifically to estrogen receptors (ERα and ERβ), which are responsible for cancer therapy. ADMET analyses secure its therapeutic potential as well safety of the drug. An isocratic method has developed by RP-HPLC-PDA (AGILENT 1100) with symmetry of 100 mm x 4.6 mm x 5 μm particle size C18 column and optimise mobile phase is methanol: 0.1% OPA (orthophosphoric acid) water ratio of 43:57% v/v. Under different conditions like acidic, alkaline, oxidative, and neutral environments, toremifene was tested for degradation. The developed method is validated in accordance with ICH guidelines. A calibration curve with an r2 value of 0.9987 has been prepared across the range of 10 to 50 μg/ml with five standard dilutions. The retention time of the drug is 5.575 minutes. The validation results are system suitability (%RSD-0.76), inter-day precision (%RSD 0.14-0.29), intraday precision (%RSD 0.08-0.34), accuracy (%RSD 0.16-0.96), and robustness (%RSD 0.16-0.35). In different intended conditions, four peaks are in 1 N HCl, two peaks in 1 N NaOH, three peaks in 10% H2O2 (1hr), and one peak in neutral. Toremifene, a Selective Estrogen Receptor Modulator (SERM), Drug pharmacokinetic properties and receptor binding affinity results are helpful in designing the analytical method. Developing the RP-HPLC-PDA method is found to be novel, simple and precise. It could be used for testing toremifene in bulk and pharmaceutical tablet dosage forms in quality control, as well as stability tests.

Assessing the efficacy of cinnamon compounds against H. pylori through molecular docking, MD Simulations and ADMET analyses.

Antibiotics are the drugs that are used for the management of microbial diseases. However, these conventional synthetic drugs can harmfully affect the human health. Since phytochemicals are extracted from natural sources and, are hence relatively safer for human health, they are the enticing alternatives in this regard. Cinnamon is also one of those plants which is being employed as herbal medication for centuries against certain microbial infections due its significant therapeutic effectiveness. A well-known pathogenic bacterium called H. pylori causes a wide range of illnesses in human body. This pathogen's pathogenicity is determined by certain virulent proteins. In this study, some of such proteins, which included virB4, virB8, and virB9 were selected to evaluate the therapeutic efficiency of cinnamon compounds. These proteins were identified in different isolates of H. pylori. The structural modelling of all these proteins were performed initially in order to proceed them for molecular docking analysis. While, the docking studies illustrated that one of the cinnamon compounds, cinnamyl acetate, showed significant binding interactions with virB4 and virB9. However, benzyl benzoate which is another cinnamon compound, docked well with virB8. Afterwards, the MD simulations were incorporated to explore the interaction motions and structural stability of all the docked complexes. In this regard, the resultant maps of Bfactor, eigenvalues and elastic network model, among other factors ensured the structural stabilities of all the respective complexes. After these crucial estimations, benzyl benzoate and cinnamyl acetate underwent the ADMET investigation to assess their pharmacokinetic characteristics. SwissADME and ADMETLab 2.0 server were employed for this investigation. The compiled findings these servers revealed that both, benzyl benzoate and cinnamyl acetate, exhibited a significant level of pharmacokinetic and drug-likeness conformity.

Molecular structural, vibrational spectra, dual descriptor, electronic transition and biological evaluations of ethyl 4‑hydroxy-3-methoxycinnamate using density functional theory

Quantum chemical, spectroscopic and bioactivity studies of pharmacologically active Ethyl 4‑hydroxy 3‑methoxy ethyl cinnamate (EHMC) were investigated. By optimizing the geometric structural parameters, it was theoretically possible to obtain the FTIR &UV–Vis absorbance of the EHMC in both protic and aprotic solvents. PED values were computed, and vibrational assignments were identified. The TD-DFT approach and the IEFPCM model were used for simulating the UV spectra of the EHMC chemical. This study presents a comprehensive analysis of molecular parameters, including topological features of electron density, Reduced density gradient (RDG), NBO hyperconjugative interaction energies, frontier molecular energies (FMO) energies, and chemical reactivity descriptors across various solvents. MEP distinguishes between nucleophilic & electrophilic locations and determines a molecule's 3D charge distribution. Electrophilic and nucleophilic strength inside a molecule explained by Fukui function and Mullikan's charge. Furthermore, drug likeness and ADMET analysis were conducted to ascertain the biological characteristics and molecular docking investigation was also performed to explore the biological function of the title substance.

The Virtual Screening of Compounds from the ZINC Database against PARP‐1 in Triple‐Negative Breast Cancer

AbstractTriple‐negative breast cancer (TNBC) is the most aggressive kind of breast cancer that has disseminated worldwide, decimating millions of people. Especially, since it is capable of forming complex mutations, the design and development of effective drugs are much needed. Clinically, though talazoparib is an FDA‐approved drug for PARP against advanced breast cancer, it has several adverse side effects such as anaemia, alopecia, neutropenia and thrombocytopenia. Herein, to understand the molecular interactions and mode of binding, 4.59 million lead‐like compounds from the ZINC database were virtually screened against poly(ADP‐ribose) polymerase‐1 (PARP‐1) protein using molecular docking. ADMET analysis were also performed for these compounds. Molecular dynamics (MD) simulations were conducted for a period of 100 ns for the best five compounds to validate the stability of the complexes. Root‐mean‐square deviation (RMSD), root‐mean‐square fluctuation (RMSF), and the radius of gyration (Rg) were analyzed and the number of hydrogen bonding interactions was identified to determine the structure and stability of these protein‐ligand complexes. Further, binding free energy calculations were performed using the molecular mechanics‐Poisson‐Boltzmann surface area (MM/PBSA) approach to identify the effective anticancer agents. Z02, Z03, and Z04 have the highest binding affinity of −19.6, −18.1, and −18.1 kcal/mol, respectively, with PARP‐1. They also have been found to strongly enhance the stability of the target. All things considered; we determine that compound Z04 is the most promising hit for TNBC.

Pharmacological evaluation and phytochemical profiling of butanol extract of L. edodes with in- silico virtual screening

L. edodes (L. edodes) is the most consumed mushroom in the world and has been well known for its therapeutic potential as an edible and medicinal candidate, it contains dietary fibers, vitamins, proteins, minerals, and carbohydrates. In the current study butanolic extract of mushroom was used to form semisolid butanol extract. The current study aimed to explore biometabolites that might have biological activities in n-butanol extract of L. edodes using FT-IR and GC–MS and LC–MS. The synergistic properties of bioactive compounds were futher assessed by performing different biological assays such as antioxidant, anti-inflammatory and antidiabetic. FTIR spectra showed different functional groups including amide N–H group, Alkane (C-H stretching), and (C = C stretching) groups at different spectrum peaks in the range of 500 cm−1 to 5000 cm−1 respectively. GC–MS profiling of n-butanol extract depicted 34 potent biomolecules among those dimethyl; Morphine, 2TMS derivative; Benzoic acid, methyl ester 1-(2-methoxy-1-methylethoxy)-2-propanol were spotted at highest range. Results indicate that L. edodes n-butanol extract showed a maximum anti-inflammatory potential 91.4% at 300 mg/mL. Antioxidant activity was observed by measuring free radical scavenging activity which is 64.6% at optimized concentration along with good antidiabetic activity. In-silico study executed the biopotential of active ingredient morphine which proved the best docking score (− 7.0 kJ/mol) against aldose reductase. The in-silico drug design analysis was performed on biometabolites detected through GC–MS that might be a potential target for sulfatase-2 to treat ruminated arthritis. Morphine binds more strongly (− 7.9 kJ/mol) than other bioactive constituents indicated. QSAR and ADMET analysis shown that morphine is a good candidates against ruminated arthritis. The current study showed that L. edodes might be used as potent drug molecules to cure multiple ailments. As mushrooms have high bioactivity, they can be used against different diseases and to develop antibacterial drugs based on the current situation in the world in which drug resistance is going to increase due to misuse of antibiotics so new and noval biological active compounds are needed to overcome the situation.

A Search for Sars‐CoV‐2 Main Protease Inhibitors: Synthesis and Docking Study of Steroidal Dinitriles

AbstractCoronaviruses are continually evolving, as evidenced by the emergence of three closely related pathogenic variants over the past two decades: SARS (2002), MERS (2012), and SARS‐CoV‐2 (2019); and the appearance of many new SARS‐CoV‐2 strains during the COVID‐19 pandemic. Hence, COVID‐19 has now become a pandemic disease; with a real possibility for the emergence of new deadly SARS‐related coronaviruses. The SARS‐CoV‐2 main protease, Mpro is an attractive drug target for the development of inhibitors against SARS type and other coronaviruses because it is essential for the viral life cycle and highly conserved among a wide range of pathogenic coronaviruses. This motivated the synthesis of novel inhibitors of Mpro, which could be the basis for COVID‐19 drug development. The synthesis of new 5,6 : 16,17‐diseco and 6,7 : 16,17‐disecoandrostane 16,17a‐dinitriles is reported. In silico ADMET analyses suggest that the synthesized compounds possess drug‐like properties with no predicted toxicities. Structural similarity analyses indicates that synthesized B,D‐diseco 16,17a‐dinitrile derivatives have potential as protease inhibitors. Molecular docking simulations suggest that B,D‐diseco 16,17a‐dinitriles could inhibit substrate binding by Mpro. The present study suggests that newly synthesized androstane 5,6 : 16,17‐diseco‐5‐keto‐6‐oic acid and 6,7 : 16,17‐diseco‐6,7‐dioic acid 16,17a‐dinitriles 8 and 11 could represent a starting point for the design of Mpro inhibitors against SARS type coronaviruses.

Exploring the Cucurbitacin E (CuE) as an Anti-Lung Cancer Lead Compound through Molecular Docking, ADMET, Pass Prediction and Drug Likeness Analysis

Exploring the Cucurbitacin E (CuE) as an Anti-Lung Cancer Lead Compound through Molecular Docking, ADMET, Pass Prediction and Drug Likeness Analysis

A Comparative Analysis on the Potential Anticancer Properties of Tetrahydrocannabinol, Cannabidiol, and Tetrahydrocannabivarin Compounds Through In Silico Approach.

The purpose of this study is to comparatively analyze the anticancer properties of Tetrahydrocannabinol (THC), Cannabidiol (CBD), and Tetrahydrocannabivarin (THCV) using In silico tools. Using SwissADME and pkCSM, the physicochemical and pharmacokinetics properties of the cannabinoids were evaluated. Protox-II was utilized for the assessment of their cytotoxicity. The chemical-biological interactions of the cannabinoids were also predicted using the Way2Drug Predictive Server which comprises Acute Rat Toxicity, Adver-Pred, CLC-Pred, and Pass Target Prediction. Both physicochemical and drug-likeness analysis using SwissADME favored THCV due to high water solubility and lower MLOGP value. On the other hand, ADMET assessment demonstrated that THC and CBD have good skin permeability while both THC and THCV exhibited better BBB permeability and have low inhibitory activity on the CYP1A2 enzyme. Furthermore, toxicity predictions by Protox-II revealed that CBD has the lowest probability of hepatotoxicity, carcinogenicity, and immunotoxicity. Contrarily, it has the highest probability of being inactive in mutagenicity and cytotoxicity. Additionally, CLC results revealed that CBD has the highest probability against lung carcinoma. The rat toxicity prediction showed that among the cannabinoids, THCV had the lowest LD50 concentration in rat oral and IV. Overall, in silico predictions of the three cannabinoid compounds revealed that they are good candidates for oral drug formulation. Among the three cannabinoids, THCV is an excellent anticancer aspirant for future chemotherapy with the most favorable results in drug-likeness and ADMET analysis, pharmacological properties evaluation, and cytotoxicity assessment results. Further study on bioevaluation of compounds is needed to elucidate their potential pharmacological activities.

Discovery of β-carboline based Derivatives through Computational Aid for the Treatment of Leishmania

Background:: Leishmaniasis is a phagocytic host cell invading, caused by leishmania species mostly found in developing nations. To treat leishmaniasis, a wide range of medications and potential vaccines are available, such as pentavalent antimonials, amphotericin, and miltefosined, but due to the lack of effective treatments, the high toxicity of chemotherapy and the growth of drug resistance linked to these diseases necessitate the urgent development of innovative therapeutic agents. β-carboline is a group of chemical compounds, and its derivatives have shown to be one of the potential candidates for the treatment of Leishmania. The carboline derivatives may have antileishmanial activity. Which act by interfering with the parasite’s DNA replication or metabolic processes, inhibiting the enzymes that are mainly responsible for the reproduction and metabolism of leishmania. Objective:: This research undertaking's present focus is on determining the existence and virtual screening of potential β-carboline derivative, which can act as an antileishmanial agent that can prevent or stop the progression of leishmania by the integration of different computational technologies such as in silico ADMET analysis and docking. Methods:: After synthesizing molecules using virtual screening, all designed compounds underwent molecular docking, and hit molecules underwent ADMET analysis. Results:: Using AutoDock Vina 1.5.6, molecular docking was carried out in the arginase receptor's active site (PDBID: 2AEB). The research and creation of compounds used virtual screening. Fifteen hits from docking experiments had high binding affinity as, in comparison to the commercially available molecule pentamidine (binding score -5.5Kcal/mol), 15 compounds (binding affinity - 7.9 to 7.0Kcal/mol). These Fifteen best hits were further examined for their ADME activity using SwissADME, and the ADME analysis identified 15 medicines as having the ideal ADME profile and improved bioavailability. Conclusion:: This research will bring up a broad spectrum of prospects for investigation into the disciplines of computational and medical research. This will facilitate the development of new antileishmanial agents that have better stability, bioavailability, and less toxicity, side effects for use in future research studies.

Screening for Active Compounds of Acorus calamus against SARS-CoV-2 Viral Protease and Mechanism Prediction.

COVID-19, caused by SARS-CoV-2, has emerged as the most destructive emerging infectious disease of the 21st century. Vaccination is an effective method to combat viral diseases. However, due to the constant mutation of the virus, new variants may weaken the efficacy of vaccines. In the current field of new coronavirus research, viral protease inhibitors have emerged as a highly regarded therapeutic strategy. Nevertheless, existing viral protease inhibitors do not fully meet the therapeutic needs. Therefore, this paper turned to traditional Chinese medicine to explore new active compounds. This study focused on 24 isolated compounds from Acorus calamus L. and identified 8 active components that exhibited significant inhibitory effects on SARS-CoV-2 PLpro. Among these, the compound 1R,5R,7S-guaiane-4R,10R-diol-6-one demonstrated the best inhibitory activity with IC50 values of 0.386 ± 0.118 μM. Additionally, menecubebane B and neo-acorane A exhibited inhibitory activity against both Mpro and PLpro proteases, indicating their potential as dual-target inhibitors. The molecular docking results confirmed the stable conformations of these compounds with the key targets and their good activity. ADMET and Lipinski's rule analyses revealed that all the small molecule ligands possessed excellent oral absorption properties. This study provides an experimental foundation for the discovery of promising antiviral lead compounds.

Deciphering the mechanisms and interactions of the endocrine disruptor bisphenol A and its analogs with the androgen receptor

Bisphenol A (BPA) and its various forms used as BPA alternatives in industries are recognized toxic compounds and antiandrogenic endocrine disruptors. These chemicals are widespread in the environment and frequently detected in biological samples. Concerns exist about their impact on hormones, disrupting natural biological processes in humans, together with their negative impacts on the environment and biotic life. This study aims to characterize the interaction between BPA analogs and the androgen receptor (AR) and the effect on the receptor's normal activity. To achieve this goal, molecular docking was conducted with BPA and its analogs and dihydrotestosterone (DHT) as a reference ligand. Four BPA analogs exhibited higher affinity (−10.2 to −8.7 kcal/mol) for AR compared to BPA (−8.6 kcal/mol), displaying distinct interaction patterns. Interestingly, DHT (−11.0 kcal/mol) shared a binding pattern with BPA. ADMET analysis of the top 10 compounds, followed by molecular dynamics simulations, revealed toxicity and dynamic behavior. Experimental studies demonstrated that only BPA disrupts DHT-induced AR dimerization, thereby affecting AR's function due to its binding nature. This similarity to DHT was observed during computational analysis. These findings emphasize the importance of targeted strategies to mitigate BPA toxicity, offering crucial insights for interventions in human health and environmental well-being.

Activity of propolis compounds as potential MMP1 and MMP2 inhibitors by in silico studies in wound healing application

Context: Matrix metalloproteinases (MMPs) play a critical role in wound healing, with higher levels seen in chronic wounds, delaying healing. Since ancient times, propolis has been widely used for traditional wound healing. However, there is still limited research on MMP1 and MMP12. Aims: To evaluate new candidates of propolis compounds for targeting MMP1 and MMP12 using in silico studies supported by experimental screening using LC-MS/MS quadrupole-time of flight (QTOF). Methods: Compounds in propolis were screened using LC-MS/MS QTOF. The 3D structure of all compounds in propolis and protein targets was prepared in Autodock and Biovia Discovery Studio. The molecular docking of all compounds in propolis was carried out using Autodock on PyRx 0.9. Drug-likeness and ADMET analysis of selected compounds in propolis with the lowest affinity were observed. Lastly, molecular dynamic simulations of the best compounds in propolis were conducted using the GROMACS 2020 package. Results: Eleven flavonoid and phenolic compounds were identified in propolis using LC-MS/MS QTOF analysis. Molecular docking simulations showed that licoflavone A and pinostrobin exhibited the lowest binding affinity to MMP1 and MMP12, respectively. Molecular dynamic simulations revealed that licoflavone A formed a more stabilized complex with MMP1, while pinostrobin formed a more stabilized complex with MMP12 than the native ligand. Conclusions: This study revealed new candidates for MMP1 and MMP12 inhibitors from propolis compounds that can enhance wound healing. It is hoped that the evidence gathered in this study provides crucial new information in exploring new wound-healing medications.

Unveiling the biomedical potential of thiophene‐derived Schiff base complexes: A comprehensive study of synthesis, spectral characterization, antimicrobial efficacy, antioxidant activity, and computational insights

In our pursuit of designing potent bioactive compounds, we synthesized six novel tellurium (IV) complexes through the condensation of 5‐methyl‐2‐thiophene carboxaldehyde and p‐nitroaniline. These compounds underwent rigorous investigation using various analytical techniques (TGA, SEM, EDAX, and powder XRD) and spectral analyses (NMR, mass spectrometry, UV–Vis, and FTIR). Spectroscopic analysis suggested an octahedral geometry for the complexes, revealing chelation through the thiophene sulfur and azomethine nitrogen atoms. Thermal analysis indicated a three‐step degradation process, ultimately leaving behind metal oxide as the end product. We conducted in‐vitro antimicrobial screening using the broth micro‐dilution method, highlighting the significant antimicrobial and antioxidant properties of complexes 3c and 3d, as well as the potent antimicrobial activity of 3b and 3f against various bacterial strains, including Candida albicans. To further substantiate our findings, we performed advanced computational analyses, including molecular docking, pharmacophore modeling, DFT, MESP, and ADMET studies. Molecular docking validated our antimicrobial results, whereas pharmacophore models enhanced our understanding of molecular interactions with proteins, potentially identifying novel bioactive compounds. Furthermore, DFT and MESP investigations underscored the superior biological efficacy of tellurium (IV) complexes over thiophene‐derived ligands, emphasizing their potential as therapeutic agents. ADMET analysis revealed their favorable profile as precursors for drug development with minimal adverse effects. In summary, our research seamlessly integrates experimental and theoretical aspects, offering innovative insights into drug design and potential applications in pharmaceuticals. This study represents a significant milestone, paving the way for future advancements in the field of pharmaceutical science.

Design, synthesis, and biological evaluation of carbazole derivatives as potent antibacterial agents targeting membrane function via FabH Inhibition

This study synthesized a series of carbazole compounds and tested their antimicrobial activity. Several of the synthesized compounds demonstrated potent inhibitory effects against Gram-negative bacteria. Molecular docking simulations with the fatty acid synthesis enzyme FabH revealed their potential antimicrobial action by interfering with fatty acid synthesis. Additionally, ADMET analysis confirmed favorable pharmacokinetic properties, providing a foundation for drug development and preclinical research. Furthermore, the optimized compound 2-(9HCarbazol-9-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide was evaluated for its inhibitory and disruptive effects on biofilms using live/dead cell staining. The results demonstrated significant inhibition and disruption of biofilms, enhancing their antimicrobial efficacy. These findings offer valuable clues for the development of new antimicrobial drugs and hold promise for addressing the challenge of antimicrobial resistance with novel therapeutic strategies.

Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies.

We provide promising computational (in silico) data on phytochemicals (compounds 1-10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1-10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1-10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.

Synthesis of Novel [{(2-Amino-5-Nitro-N-[(E)-Thiophen-2-yl-Methylidene]Aniline-κ3N1:N4:S)(Sulphato-κ2O1:O3)}Zinc(II)] Complex with Physico-Chemical and Biological Perspective Exploration: A Combined Experimental and Computational Studies.

A novel metal complex was synthesized using freshly prepared 2-Amino-5-nitro-N-[(E)-thiophen-2-yl-methylidene]aniline ligand with Zn (II) sulphate heptahydrate in a 1:1 molar ratio. The ligand and the complex were characterized using different spectroscopic techniques, and the complex was assigned a distorted square pyramidal geometry. Additionally, DNA binding assays and antibacterial activity were used to assess the biological perspectives for the synthesized complex, including the ligand and complex which was further confirmed by molecular docking. Fluorescence Spectroscopy, viscosity measurement, and adsorption measurement were used to investigate the interaction of the Zn (II) complex with CT-DNA. A comparativein vitroantibacterial activity study againstEscherichia coli, Klebsiella pneumoniae,Bacillus subtilis,andStaphylococcus aureusstrains were studied with free ligand and Zn (II) metal complex. The stable geometry of the complex was additionally established through computational simulation utilizing density functional theory, which was followed by the calculation of several electronic properties. The ADMET characteristics of the complex and ligand were also assessed using ADMET analysis. The in-silico ADMET properties pointed to a significant drug-likeness feature in the synthesized compounds, based on the Lipinski criteria.

Identification of compounds from Zingiber officinale as Novel Inhibitor for Dengue DEN2 NS2B/NS3 Serine Protease through Molecular Docking and DFT approaches

Dengue virus (DENV) is one type of virus belongs to the Flavivirus family that can be transmitted through mosquito bites. Infection with the dengue virus can cause different febrile symptoms, such as dengue fever (DD) and dengue haemorrhagic fever (DHF), with or without shock. The purpose of this study is to obtain a new compound from Zingiber officinale that is expected to have potential bioactivity against DENV-2 NS2B/NS3 serine protease. A computational approach was applied in this study; which began with docking of compounds into protein targets, followed by density functional theory, drug-likeness, and ADMET analysis. According to the calculation, it was determined that compound 9 has binding interactions with the active triad through amino acids His51, Asp75, and Ser135. Additionally, drug-likeness and ADMET analysis for compound 9 showed that it has optimal lipophilicity and, when administered orally, can achieve good bioavailability. It is indicated that compound 9 can be used as a promising and potential inhibitor for DENV-2 NS2B/NS3 serine protease.

Experimental and theoretical studies of methyl 1-(2-chloroacetyl)-4-hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate: Insights from synthesis, spectroscopic, crystal structure, Hirshfeld surface, DFT, ELF, RDG, IRI, ADMET and docking studies

Methyl 1-(2-chloroacetyl)-4‑hydroxy-2,6-diphenyl-1,2,5,6-tetrahydropyridine-3-carboxylate (compound 2) was synthesized by the condensation of 3-carboxymethyl-2,6-diphenylpiperidine-4-one with chloroacetylchloride, and characterized by FT-IR spectroscopy. Further confirmation of the molecular structure was obtained by the single crystal X-ray diffraction (SC-XRD) technique. The study revealed that the piperidine ring adopts boat conformation with equatorial orientation of two phenyl rings at C-2 and C-6. Intermolecular contacts and hydrogen bonding interactions were explored by Hirshfeld surface and 2D fingerprint analyses, showing that the major contact were H∙∙∙H (57.7 %), C∙∙∙H/H∙∙∙C (14.2 %), O∙∙∙H/H∙∙∙O (15.3), Cl∙∙∙H/H∙∙∙Cl (7.1 %) and C∙∙∙Cl/Cl∙∙∙C (12.7 %). Intramolecular interaction was examined through the Radiant density gradient (RDG), Interaction region indicator (IRI), Electron localization function (ELF), and localized orbital locator (LOL) to understand hyperconjugration and π-electrons delocalization in the molecule. DFT studies such as structure optimization, HOMO-LUMO orbital analysis and molecular electrostatic potential were conducted for the title compound. The topology of the molecular arrangement and intermolecular interaction energies were determined through 3D energy framework analysis. Subsequently, the compound 2 was subjected to ADMET analysis to extend its scope of bioavailability. Molecular docking studies were then employed using the tyrosine kinase inhibitor, epidermal growth factor receptor (EGFR) enzymes (PDB ID: 4WKQ and 6JOL). The study revealed significant interactions between the title ligand structure and active sites of selected proteins complex.

Synthesis, X-ray crystallography, computational investigation on quinoxaline derivatives as potent against adenosine receptor A2AAR

Quinoxaline represents one of the most important classes of heterocyclic compounds, which have exhibited a wide range of biological activities and industrial importance in many different fields. In this regard, we have synthetized two new quinoxaline derivatives. Their structures were confirmed by single-crystal X-ray analysis. The compounds show potent activity against adenosine receptors A2AAR based on structural activity relationship studies. Further molecular docking, molecular dynamics, ADMET analysis, and DFT (density functional theory) calculations were performed to understand the titled compound’s future drug candidacy. DFT computations confirmed the good stability of the synthesized compounds, as evidenced by the optimized molecular geometry, HOMO–LUMO energy gap, and intermolecular interactions. NBO analysis confirmed intermolecular interactions mediated by lone pair, bonding, and anti-bonding orbitals. All DFT findings were consistent with experimental results, indicating that the synthesized molecules are highly stable. These findings suggest that the synthesized compounds are promising candidates for further development as drugs for the treatment of A2AAR-related diseases. Communicated by Ramaswamy H. Sarma

In Silico Exploration of APOE4 Inhibitors: Molecular Docking and ADMET Profiling for Alzheimer's Therapy

Background: Alzheimer's disease (AD), a prevalent neurodegenerative disorder, poses significant challenges to healthcare systems worldwide. The aggregation of Amyloid-β peptide and the presence of apolipoprotein E4 (apoE4) are recognized as central factors in AD pathogenesis. Despite the availability of FDA-approved drugs, there remains a dire need for more effective and targeted treatments to combat this disease. The advent of in silico methodologies offers a promising avenue for accelerating the drug discovery process, providing a cost-effective and efficient means to screen for potential therapeutic agents. Objective: This study aimed to identify and evaluate potential inhibitors of apoE4 using in silico drug discovery methods. By targeting the interaction domain of apoE4, the study sought to discover compounds capable of reducing beta-amyloid aggregation, thus offering a novel approach to AD therapy. Methods: Computational techniques, including the Lipinski Rule of Five and ADMET filtering, were employed to screen a dataset of 80 chemical inhibitors retrieved from the NCBI database. Molecular docking was performed to assess the binding affinities and orientations of the compounds to apoE4, utilizing Phyre2 for 3D structure prediction and AutoDock Vina for docking simulations. The selection criteria for lead compounds were based on their binding energy, hydrogen bonding interactions, and compliance with drug-like properties. Results: Out of the initial 80 compounds screened, 15 were excluded based on the Lipinski Rule of Five, and an additional 43 were deemed unsuitable following ADMET analysis. Molecular docking identified two compounds, taxifolin and luteolin, exhibiting superior binding affinities to apoE4, with taxifolin showing the lowest binding energy of -7.4 kcal/mol and the highest number of hydrogen bonds in one of its conformations. Conclusion: The study successfully leveraged in silico methods to identify taxifolin and luteolin as potent inhibitors of apoE4, highlighting the potential of computational drug discovery in developing novel AD therapies. These findings pave the way for future experimental validation and clinical trials to assess the therapeutic efficacy and safety of these compounds in treating Alzheimer's disease.