Docking Studies Research Articles

Synergistic anticancer efficacy of polydatin and sorafenib against the MCF-7 breast cancer cell line via inhibiting of PI3K/AKT/mTOR pathway and reducing resistance to treatment

Polydatin (PD), a glucoside derivative of resveratrol, has been investigated for its potential to mitigate sorafenib (SOF) side effects and combat multidrug resistance in cancer treatment. The study evaluated its mechanism of action for inhibiting the protein kinase B/mTOR pathway in promoting breast cancer proliferation. The combined PD and SOF have synergistic effects with a combination index (CI) < 1 in the liver (HepG2) and breast (MCF-7) cancer cell lines. Molecular docking studies were conducted to analyze interactions of PD& SOF with protein kinases as well as apoptotic and multidrug resistance proteins, including AKT1, PI3K, mTOR, Apaf-1, and ABCB1 in MCF-7 cells. Experimental validation through real-time PCR confirmed. PD has a strong binding affinity, particularly with AKT1 (-56 kcal/mol) and ABCB1 (-27.16 kcal/mol), a gene associated with multidrug resistance. These interactions were linked to anti-proliferative anti-angiogenic effects and reduced resistance to treatment, demonstrating PD has potential therapeutic benefits. Furthermore, PD combined with SOF induced apoptosis, inhibited cell growth, and arrested MCF-7 cells in the sub-G1 phase with increased intracellular ROS. This was accompanied by reduced expression of AKT1 and ABCB1 genes, reinforcing the anticancer efficacy of PD/SOF combination therapy. In conclusion, the findings suggest that PD/SOF could serve as a promising anticancer treatment strategy, warranting further investigation for potential clinical applications and mechanistic studies in vivo.

Synthesis, Characterization, Proteolytic Activity Inhibition, ADMET Prediction, and Molecular Docking Studies of Novel Indole Derivatives as Potential SARS-CoV-2 Protease Inhibitors

Both the main protease (Mpro) and papain protease (PLpro) are fundamental enzymes in SARS-CoV-2 life cycle. In this study, we have targeted these two enzymes using novel indole derivatives as antiviral agents. The synthesized compounds were thoroughly characterized by Fourier-transform infrared spectroscopy (FT-IR), UV-vis, 1H, 13C, and 2D nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), and melting point (m.p.). The optimized structure, reactivity, and stability of the synthesized compounds were calculated using Density Functional Theory (DFT) at the B3LYP/6-31G(d,p) level. Using in silico ADMET prediction along with molecular docking, we found that the synthesized compounds presented good docking scores and very low predicted inhibition constants (Pki) from low micromolar to nanomolar ranges. In particular, compounds 10 and 11 with respective Pki values of 1.68 μM and 387.71 nM for Mpro and 402.50 nM and 27.10 nM for PLpro. These two compounds are engaged in vast range of interactions with the active sites of both enzymes. Further in vitro investigations using fluorescence resonance energy transfer (FRET) assays demonstrated that compounds 10 and 11 inhibited Mpro proteolytic activity with approximate IC50 values of 20 µM and 10 µM, respectively. These findings suggest that these new indole derivatives could serve as promising candidates for the development of drugs against SARS-CoV-2 and potentially other future coronaviruses.

Purification, characterization and molecular docking studies of analogous alpha amylase inhibitor compounds

BackgroundA large number of protein inhibitors are found in higher plants, cereals and legumes. These inhibitors are helpful in the prevention as well as medical treatment of metabolic syndromes such as type 2 diabetes. Basically, the diabetes mellitus is a chronic disorder that occurs either due to inadequate insulin secretions or when body fails to utilize the produced insulin. The alpha amylase inhibitors are termed as starch blockers. They catalyze the hydrolysis of α-(1,4)-D-glycosidic linkages of starch and other glucose polymer. They play a significant role in inhibition of the activity of salivary and pancreatic amylase in vitro and in vivo. MethodThe present study was based on the purification, characterization and molecular docking studies of the alpha amylase inhibitor isolated from the kidney bean sample. The seed sample was collected from G.B. Pant Nagar University. The crude extract was prepared, the in-vitro studies and heat stability were determined. Following it, purification was carried out using ammonium sulphate precipitation and size exclusion chromatography was done. Later, characterization and molecular docking studies of the purified sample was done after obtaining GC–MS results. ResultThe in-vitro analysis was done and noted that the inhibitory activity was 96.5 ± 0.84 % post size exclusion chromatography. The molecular weight was about 54 kDa. The molecular docking studies revealed that there were interactions between the ligand molecules (the constituents that were selected from the GC–MS chromatogram peaks based on the height and area) and the human pancreatic alpha amylase (1HNY). The hydrogen bonding as affinity binding capacity was also been observed in each of the ligand–protein interaction. ConclusionFrom the tests, it has been elucidated that the alpha amylase inhibitor isolated from the sample has a great potential to serve as an anti-diabetic drug. However, in order to check the potential effects and to explore the optimization and development of the anti-diabetic drug the in-vivo studies can also be done further.

Anti colorectal cancer activity and in silico studies of novel pyridine nortopsentin analog as cyclin dependent kinase 6 inhibitor

Nortopsentins are a vital class of deep-sea sponge metabolites which can be used as leads for antitumor agents. Although their action has been studied in several diseases’ contexts, their cytotoxic activity against colorectal carcinoma has not yet been fully investigated. Therefore, a series of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridin-5-carbonitriles 4a–j (nortopsentin analogs) was investigated for their cytotoxic activity against colorectal carcinoma. The analog 4i showed the highest antitumor activity via inducing cell cycle arrest at G1 phase. Cell cycle arrest was induced due to expression downregulation of CDK2, CDK4, and CDK6. In addition, 4i suppressed the enzymatic activity of CDK6. The theoretical study of some basic quantum factors and the geometric shape of compound 4i proved that the compound is stable and a soft molecule, in which the EHOMO and ELUMO energies were negative and had a small ∆E gap. 4i also demonstrated a high potential for oral bioavailability due to its adherence to Lipinski’s rule of five. The molecular docking studies of 4i analog showed good binding mode with CDK6 active pocket through the formation of multiple interactions with its key amino acids.

Theoretical Investigation of Nonlinear Optical Properties and Molecular Docking of Carbazoles Derived from Murraya Koenigii

AbstractIn this study, the density functional theory (DFT) method is used to theoretically investigate the nonlinear optical (NLO) properties of natural carbazoles. The selected carbazoles have significant NLO characteristics. Using the B3LYP/6‐311++G(d,p) and CAM‐B3LYP/6‐311++G(d,p) level theories, the linear optical absorption, HOMO‐LUMO energy gap, molecular electrostatic potential (MEP), and dipole moments were calculated. The first hyperpolarizability (β0), second hyperpolarizability (γ), and static and dynamic linear polarizability (α0) components were computed. Electron correlation was obtained, which was compared with NLO and docking studies showing good relation with both. All carbazole compounds demonstrate good optoelectronic qualities that promote their potential use in electronic devices, as demonstrated by the frequency‐dependent dynamic hyperpolarizabilities of the B3LYP/6‐311++G(d,p) and CAM‐B3LYP/6‐311++G(d,p) functionals at 532 and 1064 nm wavelengths. The results of the molecular docking study shows that CBZ molecules exhibit a strong affinity for both Malassezia globosa (SMG1) lipase targets. The docking data demonstrated a strong binding ability, with CBZ7 and CBZ3. This indicates that CBZ7 and CBZ3 outperform all other compounds and have a high binding capability to the target protein.

Synthesis, Characterization, Biological Activity, and Molecular Docking Study of Some New Sulfamethoxazole Derivatives.

تضمنت الدراسة في هذا البحث تحضير مركبات كيميائية جديدة مشتقة من المركب الدوائي السلفاميثوكسازول بهدف تطوير فعاليته العلاجية. تم تحضير ستة مركبات من قواعد شيف بواسطة تفاعل قواعد مانخ، كما تم تحضير مشتقين للحلقة الغير متجانسة ثيادايازين. تشخيص المركبات المحضرة والتاكد من تركيبها تم باستخدام طيف الأشعة تحت الحمراء وطيف الرنين النووي المغناطيسي و تقنية تحليل العناصربالأضافة الى قياس درجات الاتصهار واللون. تم دراسة الفعالية البايلوجية للمركبات المحضرة وتأثيرهاعلى تثبيط خمسة انواع من البكتريا وهي المكورات العنقودية الذهبية، الإشريكية القولونية، الالتهاب الرئوي كليبسيلا، السالمونيلا، والبروتيوس. أظهرت نتائج الدراسة قيم متفاوتة للفعالية البايلوجية تتراوح بين القيمة العالية الى عدم الفعالية. تم استخدام برنامج (PyRx)لحساب طاقة الارتباط للمركبات مع بروتينات البكتيريا وهي بروتين (FYV) في المكورات العنقودية الذهبية وبروتين (4H2M) في الإشريكية القولونية، وبروتين (6P4T) في السالمونيلا، حيث تم حساب قيم طاقات الارتباط وكانت اعلى قيمة لها مع البروتين (4H2M) وكانت( 9.1- كيلوكلري/مول) و مع البروتين (6P4T) كانت (7.8- كيلوكلري/مول) و اقل طاقة ارتباط وجدت مع البروتين (FYV) وكانت -5.3) كيلوكلري/مول). تم تحديد الحوامض الامينية المحيطة بالمركبات والتي ترتبط بهاغالبا بواسطة الاصرة الهيدروجينية اوبواسطة تاثرات هيدروفوبية نوع (شحنة-شحنة) او (ارين-ارين )، فضلًا على الحصول على شكل ثلاثي الابعاد لكيفية ترابط المركبات مع البروتينات. تم أيضا معرفة الكثافة الالكترونية للمركبات من خلال معرفة صفات الحوامض الامينية المحيط بالمركبات المحضرة .

Design, Synthesis, and Docking Study of Potentially Active Antimicrobial Pyrazolo[1,5‐a]pyrimidine Derivatives

AbstractCompound 4,4′‐(1,4‐phenylenebis(thiazole‐4,2‐diyl))bis(1H‐pyrazol‐5‐amine) (5) was used in the preparation of novel pyrazolo[1,5‐a]pyrimidines incorporating a thiazole moiety (6, 7b, 8, 9, and 13–18). the reactions were described via the following reactions: acetylacetone, acetanilide, diethyl malonate, ethyl cyanoacetate, 3‐(dimethylamino)‐1‐phenylprop‐2‐en‐1‐one, 2‐((dimethylamino)methylene)‐3‐oxopentane‐nitrile, 3‐(dimethylamino)‐1‐(thiophen‐3‐yl)prop‐2‐en‐1‐one, 2‐((dimethylamino)methylene)‐5,5‐dimethylcyclo‐hexane‐1,3‐dione, dimethylformamide‐dimethylacetal, and with a mixture of p‐nitro benzaldehyde/cyclohexanone, respectively. Gram‐positive bacteria B. subtilis and B. thuringiensis, as well as Gram‐negative bacteria E. coli and P. aeruginosa, were tested for the newly synthesized compounds' in vitro antibacterial activity. Their in vitro antifungal activity against fungus strains B. Fabae and F. oxysporum was also assessed. The compounds 16–18 had the strongest activity against Gram‐positive bacteria, with MIC values = 3.125 µg/mL against B. subtilis, which is equipotent to the drug reference Chloramphenicol, and MIC values = 6.25 µg/mL against B. thuringiensis, which is equipotent to the drug reference Cephalothin. Compounds (13–18) were shown to be superimposable to CNB based on their docking results, with the exception of derivative 18. Furthermore, they demonstrated a strong binding mode with DNA gyrase B's active pocket (PDB: 1KZN) by forming several contacts with the enzyme's essential amino acids in a way that was comparable to CNB.

Synthesis, In Silico Prediction, and In Vitro Evaluation of Anti-tumor Activities of Novel 4'-Hydroxybiphenyl-4-carboxylic Acid Derivatives as EGFR Allosteric Site Inhibitors.

Allosteric inhibition of EGFR tyrosine kinase (TK) is currently among the most attractive approaches for designing and developing anti-cancer drugs to avoid chemoresistance exhibited by clinically approved ATP-competitive inhibitors. The current work aimed to synthesize new biphenyl-containing derivatives that were predicted to act as EGFR TK allosteric site inhibitors based on molecular docking studies. A new series of 4'-hydroxybiphenyl-4-carboxylic acid derivatives, including hydrazine-1-carbothioamide (S3-S6) and 1,2,4-triazole (S7-S10) derivatives, were synthesized and characterized using IR, 1HNMR, 13CNMR, and HR-mass spectroscopy. Compound S4 had a relatively high pharmacophore-fit score, indicating that it may have biological activity similar to the EGFR allosteric inhibitor reference, and it scored a relatively low ΔG against EGFR TK allosteric site, indicating a high likelihood of drug-receptor complex formation. Compound S4 was cytotoxic to the three cancer cell lines tested, particularly HCT-116 colorectal cancer cells, with an IC50 value comparable to Erlotinib. Compound S4 induced the intrinsic apoptotic pathway in HCT-116 cells by arresting them in the G2/M phase. All of the new derivatives, including S4, met the in silico requirements for EGFR allosteric inhibitory activity. Compound S4 is a promising EGFR tyrosine kinase allosteric inhibitor that warrants further research.

Synthesis, Spectral Characterisation, DFT Calculations, Biological Evaluation and Molecular Docking Analysis of New Mannich Compounds Derived from Cyclopentanone

This research outlines the efficient one-pot calcium chloride-catalysed synthesis of three novel Mannich bases: M1, M2 and M3. M1 and M2 resulted from the condensing of benzaldehyde with m-nitroaniline and m-bromoaniline, respectively, in conjunction with cyclopentanone. However, M3 was obtained through the reaction of p-methoxybenzaldehyde, m-bromoaniline and cyclopentanone. The isolated compounds were thoroughly characterised using elemental analysis and various analytical and spectroscopic techniques, including the determination of their melting points, electrospray mass spectrometry (ESMS), Fourier transform infrared (FTIR), electronic spectroscopy (UV-Vis), and nuclear magnetic resonance (NMR) spectroscopy (1H- and 13C-NMR). Thermal stability (TGA and DTA analysis) of the three Mannich compounds was also examined. The newly synthesised Mannich bases exhibit remarkable potential as metal ion complexing agents and as fundamental building blocks for forming small organic molecules, particularly bioactive molecules and novel ligands for coordination chemistry. In addition to their structural significance, the biological efficacy of these compounds was assessed, revealing their excellent antimicrobial properties toward bacterial and fungal species. These activities suggest their potential use in combating microbial infections. Theoretical DFT simulations employing the B3LYP functional at the 6-311++G(d,p) level provided a thorough analysis of the stability of compounds, electrical properties, and geometry. Additionally, molecular docking studies of the Mannich compounds with two protein targets, 5IQ9 and 5VBU (both relevant for drug discovery) were performed. These studies revealed that the three Mannich compounds exhibit similar binding energies and effective interaction with both the 5IQ9 and 5VBU proteins, suggesting the potential of these Mannich compounds as dual inhibitors targeting both proteins.

Lactoperoxidase Inhibition of Celecoxib Derivatives Containing the Pyrazole Linked-Sulfonamide Moiety: Antioxidant Capacity, Antimicrobial Activity, and Molecular Docking Studies.

Celecoxib derivatives that contain the pyrazole-linked sulfonamide moiety were synthesized, and the in vitro inhibitory impacts of the aforesaid compounds against the lactoperoxidase (LPO) enzyme were researched. To this end, LPO was purified using the affinity chromatography technique with a yield of 12.63% (319.23-fold). The results showed that the aromatic pyrazole compound (compound 1) containing 2,3-dimethoxyphenyl functional groups was the most effective LPO inhibitor with a Ki value of 3.2 ± 0.7 nM and noncompetitive inhibition type. The second section of the study tested the previously synthesized compounds to reveal their antioxidant and antimicrobial properties. The above-mentioned compound also displayed high activity levels compared to standard antibiotics and antifungals, while all other compounds also showed antibacterial activity. In the three antioxidant methods we used, the compound with 2,5-dimethoxy phenyl groups obtained from the reaction of the aromatic pyrazole compound with propionic anhydride in the presence of NEt3 displayed the highest activity. Furthermore, molecular docking and molecular mechanics studies were conducted to complement and validate the experimental findings. The results obtained from these computational analyses are highly consistent with the experimental data.

Targeting c-Met in Cancer Therapy: Unravelling Structure-Activity Relationships and Docking Insights for Enhanced Anticancer Drug Design.

The c-Met receptor, a pivotal player in oncogenesis and tumor progression, has become a compelling target for anticancer drug development. This review explores the intricate landscape of Structure-Activity Relationship [SAR] studies and molecular binding analyses performed on c-Met inhibitors. Through a comprehensive examination of various chemical scaffolds and modifications, SAR investigations have elucidated critical molecular features essential for the potent inhibition of c-Met activity. Additionally, molecular docking studies have provided invaluable insights into how c-Met inhibitors interact with their target receptor, facilitating the rational design of novel compounds with enhanced efficacy and selectivity. This review highlights key findings from recent SAR and docking studies, particularly focusing on the structural determinants that govern inhibition potency and selectivity. Furthermore, the integration of computational methodologies with experimental approaches has accelerated the discovery and optimization of c-Met inhibitors, fostering the advancement of promising candidates for clinical applications. Overall, this review underscores the pivotal role of SAR and molecular docking studies in advancing our understanding of c-Met inhibition and guiding the rational design of next-generation anticancer agents targeting this pathway.

Computational Docking studies of Phenyl Acetic Acid Derivatives with Biological Targets, DNA, Protein and Enzyme

Phenyl acetic acid (PAA) is a well-known biomolecule used in antibiotics and drugs. To elucidate the binding modes of PAA and its derivatives with DNA, Pim kinase protein, and urease enzymes, molecular docking studies were conducted. The results revealed that PAA and its derivatives intercalate with DNA, disrupting its structure and potentially affecting replication, transcription, and repair processes. The 3-chloro-PAA showed the highest docking score (-7.809) and significant polar interactions with DNA residues. For Pim kinase, the compounds exhibited polar interactions with key residues, with 2-propyl PAA demonstrating notable inhibitory effects. Similarly, PAA derivatives interacted effectively with urease enzymes, with the 4-propyl-PAA showing a strong docking score (-8.5250). Overall, the meta-substituted PAAs exhibited superior binding interactions compared to ortho and para-substituted derivatives, suggesting their potential as effective inhibitors for these biological targets.

'Bhim Kol (Musa Balbisiana)' Wine: Chemical Profiling and Antidiabetic Properties with MD Simulation Insights.

Musa balbisiana (Bhim Kol), an exotic fruit that offers numerous benefits can be fermented to obtain a unique indigenous wine. This study explores the fermentation of Musa balbisiana (Bhim Kol) fruit to produce a unique indigenous wine using strain of Saccharomyces cerevisiae and sugar over a 21-day period. Chemical profiling via GC-MS analysis revealed the presence of major volatile compounds such as butan-1-ol, propanoic acid, 2-phenylethanol, oxolane-2,5-dione etc. The wine exhibited in vitro α-glucosidase inhibition activity with an IC50 value of 8.56±0.14 μg/mL and antioxidant properties (DPPH⋅ scavenging activity (AAR) of 1.29±0.18 mM TRE). Molecular docking and simulation studies indicated potential binding of volatile compounds like 4-Hydroxy-3-methoxybenzoic acid, 2-phenylethanol, butan-1-ol and butane-2,3-diol with α-glucosidase enzyme. The study suggests the medicinal potential of the wine and its suitability for commercial production in the winery industry. Further studies are warranted to explore its full medicinal benefits.

Deciphering Plasmodium Condensin Core Subunits of Structural Maintenance of Chromosomes 2 (SMC2) as a Putative Drug Target for Antimalarial Drug

Background: The structural maintenance of chromosomes (SMC) proteins plays a noteworthy role in chromosome dynamics. Several recent studies reported that the condensin core subunits of structural maintenance of chromosomes 2 (SMC2) play important roles in the atypical mitosis of the Plasmodium life cycle and may perform different functions during different proliferative stages. For eukaryotes, the structural maintenance of chromosomes (SMC) proteins are divided into six subunits and form three heterodimers of structural maintenance of chromosomes (SMC1/3) cohesion complex, structural maintenance of chromosomes (SMC2/4) condensin complex, and structural maintenance of chromosomes (SMC5/6) complex for chromosome cohesion, condensation, and DNA damage repair, respectively. Objective: The objective of this study was to investigate the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a putative drug target of malariacausing Plasmodium falciparum. Methods: In this study, we investigated the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a putative drug target of malaria-causing P. falciparum by using in-silico approaches like Homology modeling, in-silico evaluation of the modeled structure, molecular docking study to investigate the interaction of receptor-ligand, and molecular dynamic simulation study with MM calculation. Results: We reported the structural maintenance of chromosomes 2 (SMC2) protein of P. falciparum as a potent drug target that can pave the way for novel drug discovery to mitigate malaria. Conclusion: In-silico-based studies play a significant role in understanding any protein for potential drug development.

Virtual screening and lead optimization of Desmostachya bipinnata-derived FGFR inhibitors for oral squamous cell carcinoma management

BackgroundOral cancer remains a major global health challenge with limited therapeutic options, highlighting the need for novel treatments. Phytochemicals derived from Desmostachya bipinnata (Db), a plant used in traditional Chinese medicine for its anti-inflammatory and analgesic properties, have demonstrated potential anti-cancer effects. However, their mechanisms of action, particularly in targeting Fibroblast Growth Factor Receptor (FGFR) in oral cancer, are not well characterized. ObjectiveThis study aimed to leverage in-silico drug design methodologies to identify bioactive compounds from Db with potential FGFR-inhibiting activity for the treatment of oral cancer. MethodologyAn MTT assay was conducted using KB cell lines to evaluate cytotoxic effects, while thirty-eight phytochemicals from Db were screened through in silico approaches for their pharmacokinetics, toxicity, and drug-likeness. Molecular docking studies were performed to assess binding affinities to the FGFR protein. The biological activity and toxicity of the compounds were predicted to prioritize candidates for further investigation. ResultsFourteen compounds were identified as promising candidates based on their drug-like properties, favourable pharmacokinetic profiles, significant FGFR binding affinities, and predicted anti-cancer activity. These compounds also demonstrated potential for oral bioavailability and central nervous system penetration, supporting their candidacy for further drug development. Notably, the traditional use of Desmostachya bipinnata in TCM emphasizes its role in enhancing overall vitality and immune function, which may synergize with the identified FGFR-inhibiting properties in the context of oral cancer treatment ConclusionThe phytochemicals from Desmostachya bipinnata exhibit significant potential as FGFR-targeted therapeutic agents for oral cancer. Further experimental validation and optimization of these lead compounds could contribute to the development of novel, effective treatments for oral cancer and related conditions

Triazole scaffold-based DPP-IV Inhibitors for the management of Type-II Diabetes Mellitus: Insight into Molecular Docking and SAR.

Diabetes mellitus, characterized as a chronic metabolic disorder or a polygenic syndrome; is increasing at a very fast pace among every group of the population worldwide. It arises due to the inability of the body to produce enough insulin (the hormone responsible for controlling blood sugar levels) or inability to utilize the insulin, leading to hyperglycaemic condition, which, if left uncontrolled gives rise to chronic microvascular and macrovascular complications like retinopathy, neuropathy, nephropathy, coronary artery disease, cognitive impairment, etc. Several therapeutic approaches are available for the treatment of diabetes; among which dipeptidyl peptidase (DPP-IV) inhibitors (gliptins) hold a significant place. DPP-IV is a multifunctional enzyme or a serine exopeptidase that plays an imperative role in cleaving bioactive molecules. DPP-IV causes the breakdown of incretin hormone (GLP-1: Glucagon-like peptide 1 and GIP: Glucose-dependent insulinotropic peptide) that is essential for controlling glycaemic levels in the body. Inhibition of DPP-IV enzyme (DPP-IV inhibitors: Sitagliptin, Saxagliptin, Linagliptin, Alogliptin) prevents this breakdown, thereby controlling blood glucose levels and saving the patients from deleterious effects of prolonged hyperglycaemic conditions. Triazole-based DPP-IV inhibitors are a significant class of drugs used to treat Type 2 diabetes mellitus in a dose-dependent manner. Clinical trials have demonstrated their efficacy as monotherapy or in combination with other antidiabetic agents. This review highlights the molecular docking studies and structure-activity relationship of potential synthetic derivatives that may act as lead molecules for future drug discovery and yield drug molecules with enhanced efficacy, potency and reduced toxicity profile.

Synthesis, Biological Evaluation, Molecular Docking Studies and ADMET Prediction of Oxindole-Based Hybrids for the Treatment of Tuberculosis.

With a projected mortality toll of 1.4 million in 2019, tuberculosis (TB) continues to be a significant public health concern around the world. Studies of novel treatments are required due to decreased bioavailability, increased toxicity, increased side effects, and resistance of several first- and second-line TB therapies, including isoniazid and ethionamide. This study reports the synthesis of oxindole-based hybrids as potent InhA inhibitors targeting Mycobacterium tuberculosis. The synthesized compounds (5a-5e and 8a-8c) were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis and nontuberculous mycobacteria (NTMs), viz. M. abscessus (ATCC 19977), M. fortuitum (ATCC 6841), and M. chelonae (ATCC 35752) using the Microplate Alamar Blue Assay (MABA). Molecular docking studies were performed using AutoDock Vina to explore the binding interactions of these compounds with the InhA enzyme (PDB: 2NSD). Additionally, biochemical and histopathological studies were conducted to assess the hepatotoxicity of the lead compounds. Insilico molecular properties and ADMET properties of the synthesized compounds were predicted using SwissADME and Deep-PK online tools to assess their drug-likeness. Among the tested compounds, 8b exhibited significant anti-mycobacterial activity with a minimum inhibitory concentration (MIC = 1 μg/mL) comparable to the reference drug ethambutol. Further, the compound demonstrated a binding affinity and orientation similar to the reference inhibitor 4PI, indicating its potential as a potent InhA inhibitor, and was found to be stabilized within the binding pocket of InhA through H-bonding, hydrophobic and van der Waal's interactions. Besides, the compounds hepatotoxicity assessment studies depicted that 8b showed no significant liver dysfunction or damage to liver tissues. Additionally, 8b adhered to Lipinski's rule of five and Veber's rule, displaying favourable pharmacokinetic and drug-like properties, including high human intestinal absorption, distribution, and acceptable metabolic stability and excretion. Compound 8b emerged as a promising candidate for further optimization and development as a therapeutic agent for tuberculosis, offering a new avenue for tackling tuberculosis.

Molecular docking study of modified isoniazid compounds on mycolic acid synthase in the cell wall of mycobacterium tuberculosis

Using the isoniazid in antituberculosis therapy can lead to mutations in the KatG and inhA genes of Mycobacterium tuberculosis, resulting in the development of resistance and necessitating modifications to the isoniazid compound. This study aims to assess the potential and level of toxicity of modified compounds, namely 4-pyridine carboxylic acid, pyridine aldehyde, and methyl pyridine, on the mycolic acid receptor through a molecular docking approach. PyRx was employed for the docking process using a protocol with an exhaustiveness of 106 and a center grid box at X=42.424, Y=22.4321, and Z=46.6391. Additionally, the ProTox-II website was used to determine the toxicity level of the test compounds. The results obtained from this research consist of the respective affinity values of the test compounds: -6, -5.4, and -5.2 kcal/mol. The toxicity levels of the test compounds are as follows: class 5, class 4, and class 4. All test compounds interact with amino acids on the target protein, specifically with residue numbers Histidine (HIS A:8), Phenylalanine (PHE A:142) through hydrogen bonding, Leucine (LEU A:95) through pi-Sigma (π) bonding, and Valine (VAL A:12) through pi-Alkyl (π) bonding. In conclusion, the 4-pyridine carboxylic acid compound exhibits potential as a promising drug candidate but comes with a high level of toxicity

Synthesis, spectroscopic, computational, topology, and molecular docking studies on N,N'-(4-methyl-1,3-phenylene)bis(1-(2,4-dichlorophenyl)methanimine)

The study extensively examined N,N'-(4-methyl-1,3-phenylene)bis(1-(2,4-dichlorophenyl)methanimine) (6D). Advanced spectroscopic techniques, including IR, Raman, NMR, and UV-VIS spectroscopies, were employed to analyse the molecule. The Schiff base was ultimately confirmed using NMR spectrum analysis. The UV-VIS study revealed a notable bathochromic change in the compound, indicating their electronic transitions. By using the HOMO–LUMO bond gap the titled compound reactivity sites were identified. The compound 6D HOMO–LUMO band gap is 3.70 eV. Various wave function investigations like MESP, HOMO–LUMO, RDG, ELF, LOL, and ALIE were conducted to elucidate the distribution of electronic charge, providing valuable insights into the behaviour of molecules. The biological probability of the synthesised compound was extensively assessed using a docking study. Using MEP and HOMO–LUMO investigations, we confirm nucleophilic and electrophilic attacking sites. In the docking study, the protein Bovine cytochrome bc1 complex stigma Tellin bound (PDB ID–1PP9) was downloaded. The docking study identified the most stable minimum binding energy is –6.26 kcal/mol.

Evaluation of Rhus Tox, a homeopathic formulation for treatment of Parkinson’s and Alzheimer’s disease: a network pharmacology and ex-vivo approach

Rhus toxicodendron, commonly known as Rhus tox, is a potent homeopathic medication widely used in the treatment of rheumatoid arthritis and is claimed to have potential benefits for neurodegenerative disorders. Given the ability of homeopathic medications to address the root causes of diseases, our study aimed to evaluate Rhus tox for Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) using in-silico, ex-vivo, and network pharmacology approaches to obtain comprehensive information on its multi-component and multi-target effects. Phytoconstituents of Rhus tox were collected from PubMed and screened for ADMET properties. Targets for these constituents were predicted using the Binding Database and DisGeNET, resulting in 61 targets for Parkinsonism and 85 targets for alzhiemer’s disease. Protein-protein interactions (PPIs) were analysed using the STRING database. A Venn diagram was constructed for all these targets, and 5 out of 13 common targets were selected for docking studies. From these analyses, kaempferol and quercetin were identified as promising neuroprotective agents with good blood-brain barrier (BBB) permeation. The docking studies validated these predictions as most of the constituents showed good binding affinity with EGFR, SNCA and MAO-B. It was further validated using MAO inhibition assay, in which Quercetin was found to be highly efficacious, with an IC50 value of 32.69 μg/mL among the other flavonoids studied for MAO inhibition assay. The Rhus Tox also showed MAO inhibition assay similar to the standard seligiline. To conclude, we can propose that Rhus Tox primarily acts on the dopaminergic pathway, serotonergic pathway, and EGFR signaling pathway. Further in vitro and in vivo studies are needed to confirm the mechanism action and efficacy of Rhus Tox for treatment of neurodegenerative diseases.