Docking Score Research Articles

Synthesis and Molecular Modeling Studies and In silico Anthelmintic Activity of N-(benzo[d]thiazol-2-yl)-3- Chloro-6-Nitrobenzo[b]thiophene- 2-Carboxamide Derivatives

Helminthiasis is a noteworthy health problem with increased morbidity. In this manuscript, we developed a series of N-(benzo[d]thiazol-2-yl)-3-chloro-6-nitrobenzo[b]thiophene-2-carboxamide derivatives (3a-f) and evaluated against Pheretima posthuma and Perionyx excavates helminths. The compounds 3a-f were synthesized by reaction of 3-chloro-6-nitrobenzo[b]thiophene-2-carbonyl chloride (1) and appropriate benzo[d]thiazol-2-amines (2a-f) presence of pyridine. A compound 1 was synthesized by reaction of 4-nitro-cinnamic acid reacts with thionyl chloride in the presence of pyridine and chlorobenzene. Results showed that molecule 3c observed with maximum anthelmintic against P. excavates and P. posthuma with mean paralyzing time of 13.15 min and 17.39 min and mean death time of 16.17 min and 20.14 min, respectively. Molecular docking against 3VRA receptor showed that molecule 3c showed maximum dock score of -7.3 kcal/mol and reference standard albendazole with dock score of -5.5 kcal/mol. Molecular dynamic simulation data reflected the stable ligand-receptor interaction. As per Molecular Mechanics Poisson-Boltzmann Surface Area analysis, maximum free binding energy of -31.224 kJ/mol showed by 3c and ARG 76 was the most contributed residue. Density functional theory calculation data confirmed that most of the molecules were soft molecules with electrophilic nature. Molecular electrostatic potential data of 3c showed that terminal nitro group, ketone group, -COO group of ester were responsible for electrophilic attack and benzo[b]thiophne and -NH groups were responsible for nucleophilic attack. The activity profile of the synthesized molecules against helminthes was 3c >3e >3d >3f >3b >3a.. KEYWORDS :Molecular docking, Molecular dynamic simulation, Molecular mechanics poisson-boltzmann surface area, Density functional theory, Anthelmintic activity.

Synthesis, molecular docking, and anticancer study of some new [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines

A new series of fused [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines was synthesized by the reaction of 3-hydrazino- 5-phenyl-4H-1,2,4-triazole-4-amine [4] with various aromatic aldehydes in present piperidine as catalyst. The newly synthesized compounds exhibited an anticancer effect when docked inside the C-Met tyrosin kinase receptor, as shown by their docking scores ranging from -6.058 to -4.853 Kcal/mol. In contrast, crizotinib binding affinity is -3.211 Kcal/mol for anticancer efficiency. Preliminary anticancer testing revealed that the compounds exhibit activity agents against hepG2 and HdFn cell lines. It showed the highly cytotoxic effect of the synthesized compound on the hepG2 Cell line (μg/mL 99.73), where no cytotoxic effect was observed on normal human cells (HdFn Cell line).. KEYWORDS :Molecular docking anticancer, Triazolotetrazine, Triazolylhydrazine

Employing Hexahydroquinolines as PfCDPK4 Inhibitors to Combat Malaria Transmission: An Advanced Computational Approach.

Existing antimalarial drugs primarily target blood-stage parasites, but there is a need for transmission-blocking drugs to combat malaria effectively. Plasmodium falciparum Calcium-dependent Protein Kinase 4 (CDPK4) is a promising target for such drugs. This study employed advanced in silico analyses of hexahydroquinolines (HHQ) derivatives to identify PfCDPK4 inhibitors capable of disrupting malaria transmission. Structure-based virtual screening (SBVS) was employed to discover HHQ derivatives with the highest binding affinities against the 3D structure of PfCDPK4 (PDB 1D: 4QOX). Interaction analysis of protein-ligand complexes utilized Discovery Studio Client, while druglikeness and ADMET properties were assessed using SwissADME and pkCSM web servers, respectively. Quantum mechanical calculations of the top hits were conducted using density functional theory (DFT), and GROMACS was employed to perform the molecular dynamics (MD) simulations. Binding free energy was predicted using the MMPBSA.py tool from the AMBER package. SBVS identified ten best hits possessing docking scores within the range of -11.2 kcal/mol and -10.6 kcal/mol, surpassing the known inhibitor, BKI-1294 (-9.9 kcal/mol). Among these, 4-[4-(Furan-2-carbonyl)piperazin-1-yl]-1-(naphthalen-2-ylmethyl)-2-oxo-4a,5,6,7,8,8a-hexahydroquinoline-3-carbonitrile (PubChem ID: 145784778) exhibited the highest binding affinity (-11.2 kcal/mol) against PfCDPK4. Comparative analysis of this compound with BKI-1294 using advanced computational approaches demonstrated competitive potential. These findings suggest the potential of 4-[4-(Furan-2-carbonyl)piperazin-1-yl]-1-(naphthalen-2-ylmethyl)-2-oxo-4a,5,6,7,8,8a-hexahydroquinoline-3-carbonitrile as a promising PfCDPK4 inhibitor for disrupting malaria transmission. However, further experimental studies are warranted to validate its efficacy and safety profile.

Molecular hybridization of pyridine-thiophene clubbed isoxazole heterocycle in a single entity: Synthesis, antimicrobial, antitubercular, molecular docking and ADMET analysis

In the present study, 10 new hybrid pyridine-thiophene clubbed isoxazole derivatives (8a-j) were synthesized from the reaction of benzylideneacetophenones (7a-j) with hydroxylamine hydrochloride in alkaline medium. The synthesized compounds were tested for in vitro antimicrobial and antitubercular properties. Four promising new lead compounds such as 8c, 8d, 8f, and 8h endowed with excellent antimicrobial and antitubercular activity. In addition, the docking score for the most active compounds 8b, 8e, 8g, and 8h was found to be -8.6 to -8.8 kcal/mol demonstrating its favorable accommodation within the active site of the PknB enzyme.. KEYWORDS :ADMET analysis, Antimicrobial, Antitubercular, Molecular docking, Molecular hybridization, Pyridine-thiophene clubbed isoxazole.

Bioassay-guided fractionation and in vitro and in silico biological activities of 2,4-di-tert-butylphenol isolated from Nocardiopsis sp. strain LC-8

In this study, an actinomycete strain was isolated from freshwater soil sediments to produce bioactive metabolite with a broad array of biological activities. Initially, preliminary antibacterial screening of isolate was performed by perpendicular streak method which showed the growth inhibition of all tested bacterial pathogens. Based on the culture characteristics, morphological identification, and 16S rRNA gene sequencing, the isolate was identified as Nocardiopsis sp. strain LC-8. Ethyl acetate extract of strain LC-8 showed potential antibacterial activity against tested bacterial pathogens with a maximum zone of inhibition of 16.98±0.57 mm against Staphylococcus aureus. After column chromatography, fraction 2 (F2) of the extract exhibited prominent growth inhibition activity against all tested bacterial and fungal pathogens. Antioxidant activity of F2 showed potent free radical scavenging activity with low IC50 values (DPPH - 278.15±0.35 μg/mL, ABTS - 367.55±1.13 μg/mL, and FRAP - 347.48±1.35 μg/mL). Total phenolic content of F2 was quantified as 362.44±1.25 mg gallic acid equivalent/gram extract. As per spectral analyses, the isolated compound from F2 was identified as 2,4-di-tert-butylphenol which further induced cytotoxic (IC50 value - 17.5±1.5 μg/mL) and apoptosis activity against MCF-7 cells. Molecular interaction studies of 2,4-di-tert-butylphenol with target proteins of pathogens and cancer cells displayed good docking score values. Finally, molecular dynamics simulation was performed to determine the stable structure of the protein-ligand system and effectiveness of 2,4-di-tert-butylphenol against the target protein. In conclusion, Nocardiopsis sp. strain LC-8 may act as a promising source for the production of 2,4-di-tert-butylphenol aiding diverse therapeutic roles.

Investigation of Cissus populnea as a Potential Therapeutic Agent for Erectile Dysfunction.

Cissus populnea (CP) is a plant reported to possess an erection-enhancing ability, though mechanisms remain unclear. Drugs targeting phosphodiesterase 5 (PDE5) inhibition, such as sildenafil, have been employed to treat erectile dysfunction (EDRF), but they are associated with several complications. This study investigated the effect of C. populnea extracts (aqueous and saponin-rich) on the activity and gene expressions of proteins related to erection. PDE5, Nitric oxide synthase (NOS) and androgen receptor (AR) genes were studied using RT-PCR on CP-treated paroxetine-induced ERDF-rats. It also employed Schrödinger suites for investigations such as molecular and induced-fit docking, MMGBSA, ADMET, and QSAR profiling of CP-phytocompounds. C. populnea extracts reduce the activity and downregulate the expression of the PDE5 gene while upregulating the expressions of AR and NOS genes in the ERDF-rats relative to the control group. Five (leading) compounds with induced-fit docking (IFD) scores in kcal/mol, namely, stigmasterol (-638.73), daucosterol (-644.73), furostanol (-639.29), papaverine (-639.03), and capsaicin (-642.88), had better docking scores of -9.936, -9.824, -9.064, -8.863, and -8.736 kcal/mol, respectively, compared with those of sildenafil (-8.611 kcal/mol). They also showed an excellent ADMET profile, satisfying Lipinski's rule of five. The MMGBSA predictions revealed that stigmasterol, daucosterol, papaverine, and capsaicin had binding free energies of -45.29, -59.14, -50.63, and -50.47 kcal/mol, respectively, suggesting that they are significant inhibitors of PDE5. The QSAR model revealed that lead compounds possess good pIC50 values. These results indicate that C. populnea is a more promising possible treatment for controlling EDRF and deserves further research.

The Inhibiting Effect of GB-2, (+)-Catechin, Theaflavin, and Theaflavin 3-Gallate on Interaction between ACE2 and SARS-CoV-2 EG.5.1 and HV.1 Variants.

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, continues to pose significant global health challenges. The results demonstrated that GB-2 at 200 μg/mL effectively increased the population of 293T-ACE2 cells with low RBD binding for both SARS-CoV-2 Omicron EG.5.1 and HV.1 variants by dual-color flow cytometry, indicating its ability to inhibit virus attachment. Further investigation revealed that (+)-catechin at 25 and 50 μg/mL did not significantly alter the ACE2-RBD interaction for the EG.5.1 variant. In contrast, theaflavin showed inhibitory effects at both 25 and 50 μg/mL for EG.5.1, while only the higher concentration was effective for HV.1. Notably, theaflavin 3-gallate exhibited a potent inhibition of ACE2-RBD binding for both variants at both concentrations tested. Molecular docking studies provided insight into the binding mechanisms of theaflavin and theaflavin 3-gallate with the RBD of EG.5.1 and HV.1 variants. Both compounds showed favorable docking scores, with theaflavin 3-gallate demonstrating slightly lower scores (-8 kcal/mol) compared to theaflavin (-7 kcal/mol) for both variants. These results suggest stable interactions between the compounds and key residues in the RBD, potentially explaining their inhibitory effects on virus attachment. In conclusion, GB-2, theaflavin, and theaflavin 3-gallate demonstrate significant potential as inhibitors of the ACE2-RBD interaction in Omicron variants, highlighting their therapeutic promise against COVID-19. However, these findings are primarily based on computational and in vitro studies, necessitating further in vivo research and clinical trials to confirm their efficacy and safety in humans.

Unveiling the anticancer potential of novel spirooxindole-tethered pyrazolopyridine derivatives

In the current medical era, human health is confronted with various challenges, with cancer being a prominent concern. Therefore, enhancing the therapeutic arsenal for cancer with a constant influx of novel molecules that selectively target tumor cells while displaying minimal toxicity toward normal cells is imperative. This study delves into the antiproliferative and EGFR kinase inhibitory activities of newly reported spirooxindole-pyrazolo[3,4-b]pyridine derivatives 8a-h and 10a-h. The inhibitory effects on the growth of human cancer cell lines A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma), and A-431 (skin epidermoid carcinoma) were evaluated, and the SAR has been clarified through analysis. With IC50 values in the single-digit micromolar range, compounds 8b, 8d, 10a-b, and 10d were shown to be the most effective antiproliferative candidates against the studied cancer cell lines. They also exerted negligible cytotoxicity (with selectivity scores between 8.63 and 30.02) against the human lung MRC5 cell line. Additionally, we investigated the potential inhibitory action of compounds 8b, 8d, 10a-b, and 10d on EGFR and VEGFR-2. 10a was this investigation’s most effective EGFR inhibitor, with an IC50 value of 0.54 μM. Ultimately, the molecular docking analysis of congener 10a highlighted its effective suppression of EGFR by examining its binding mode and docking score compared to Erlotinib. These findings underscore the potential of spirooxindole-pyrazolo[3,4-b]pyridine derivatives as promising anticancer agents targeting EGFR kinase.

Exploration of date palm (Phoenix dactylifera) bioactivity as anti-SARS-CoV-2: in silico study

The COVID-19 pandemic has highlighted the need for innovation and the development of antiviral agents. One plant with potential antiviral properties is the date palm (Phoenix dactylifera). However, research on the antiviral activity of dates against SARS-CoV-2 is limited. This study aims to assess the antiviral potential of compounds found in date palm fruit using a molecular docking method. Specifically, we compare these compounds to the antiviral drugs ritonavir and nirmatrelvir in their ability to inhibit SARS-CoV-2 proteins. The molecular docking analysis was conducted using various tools and software, including Autodock Vina, DS Visualizer, Autodock Tools, Python, and Marvin Sketch. The results of the study indicate that compounds such as apigenin, diosmetin, and luteolin have strong potential as antiviral agents. The binding affinity of apigenin in date fruit with various SARS-CoV-2 proteins is as follows: -7.6 kcal/mol for 3CL-Pro, -8.7 kcal/mol for Nsp3, -5.7 kcal/mol for PD-ACE-2, and -7.0 kcal/mol for RBD-S. Diosmetin exhibits similar binding affinities with these proteins: -6.7 kcal/mol, -8.5 kcal/mol, -5.6 kcal/mol, and -7.2 kcal/mol, respectively. Luteolin also shows strong binding affinities: -7.9 kcal/mol, -8.6 kcal/mol, -5.7 kcal/mol, and -7.3 kcal/mol. In comparison, nirmatrelvir achieved docking scores of -7.2 kcal/mol, -7.5 kcal/mol, -5.1 kcal/mol, and -6.3 kcal/mol with the same proteins, while ritonavir scored -7.0 kcal/mol, -8.2 kcal/mol, -5.6 kcal/mol, and -6.7 kcal/mol, respectively. Apigenin, diosmetin, and luteolin demonstrate stronger potential than nirmatrelvir and ritonavir, as evidenced by their lower docking scores when compared to these drugs.

Antibacterial Activity, Toxicity and Drug-Likeness Profiles of Woodfordia fruticosa-Derived Metabolites Using Computational-Aided Drug Design Platform

This study presents a comprehensive investigation into the phytoconstituents reported from Woodfordia fruticosa (L.) Kurz leaf and flower extracts using gas chromatography-mass spectrometry (GC-MS) analysis, along with some existing phytochemicals, to explore their potential antibacterial properties through molecular docking studies. Followed by bio-assay-guided leave and flower extraction with two solvent systems, i.e., methanol (polar) and petroleum ether (non-polar), was used and further subjected to GC-MS to identify and quantify various secondary metabolites. Based on spectral intensity and volume area, a total of 28 compounds (P1 to P28) have been selected from GC-MS analyses, and an additional 14 compounds (P29 to P42) from previous reports were selected for molecular docking studies against DNA gyrase subunit B (GryB) of Escherichia coli (PDB ID: 7P2M) and Staphylococcus aureus (PDB ID: 5D7R) with novobiocin as the standard. Further, docking score or binding affinity (kcal/mol.) of each ligand were investigated, where the 4,5-dihydro-4,4-undeca methylene-2-phenyl-1,3-oxazin-6-one (P20) with a docking score of -8.4 kcal/mol., from the GC-MS-derived group and the chrysophanol-8-O-β-d-glucopyranoside (P37) with a docking score of -9.7 kcal/mol., from existing phytochemical groups were reported as potential antibacterial. The predicted toxicity and drug-ability profiles also suggested that GC-MS-derived candidates displayed comparatively higher non-toxic profiles but lower drug-likeness profiles than existing groups. This integrative approach explores the phytochemical profiles of W. fruticosa responsible for antibacterial activity of the crude extracts and providing insights into in selection of lead antibacterial agent through cost-effective computer-aided drug design platform to accelerate antibacterial drug discovery with higher chance of experimental success.

Targeting SARS-CoV2 spike glycoprotein: molecular insights into phytocompounds binding interactions – in-silico molecular docking

This study utilized small molecular characterization and docking study to evaluate the binding affinity of seven antiviral phytocompounds with the SARS CoV-2 variants (SARS-CoV-2 Spike Glycoprotein, SARS-CoV-2 Spike Protein Variant in 1-RBD, Alpha Variant SARS-CoV2- Spike Protein). The results revealed that five of seven compounds, possesses excellent drug lead property reveled through in-silico ADMET analysis. In addition, six of seven except D-Glucosamine, exhibited excellent binding affinity. Six ligands possess significant binding affinity towards SARS-CoV-2 variants 6VXX, 7LWV and 7R13, which is certainly greater than Remdesivir. Fagaronine found to be the best drug candidate against SARS-CoV-2 variants, It was found that −7.4, −5.6 and −6.3 is the docking score respectively. Aranotin, Beta aescin, Gliotoxin, and Fagaronine formed hydrogen bonds with specific amino acids and exhibited significant binding interactions. These findings suggest that these phytocompounds could be promising candidates for developing antiviral therapies against SARS-CoV-2. Moreover, the study underscores the importance of molecular docking in understanding protein-ligand interactions and its role in drug discovery. The documented pharmacological properties of these compounds in the literature further support their potential therapeutic relevance in various diseases.

In silico analysis of polyphenols modulate bovine PPARγ to increase milk fat synthesis in dairy cattle via the MAPK signalling pathways.

This study investigates the potential phytochemicals that modulate bovine peroxisome proliferator-activated receptor gamma (PPARγ) and the Mitogen-Activated Protein Kinase (MAPK) pathways to enhance milk fat production in dairy animals. Bovine PPARγ, a key member of nuclear hormone receptor superfamily, plays a vital role in regulating metabolic, cellular differentiation, apoptosis, and anti-inflammatory responses in livestock, while the MAPK pathway is contributory in cellular processes that impact milk fat synthesis. This approach involved an all-inclusive molecular docking analysis of 10,000 polyphenols to identify potential PPARγ ligands. From this extensive screening, top 10 compounds were selected that exhibited the highest binding affinities to bovine PPARγ. Particularly, Curcumin sulphate, Isoflavone and Quercetin emerged as the most promising candidates. These compounds demonstrated superior docking scores (-9.28 kcal/mol, -9.27 kcal/mol and -7.31 kcal/mol respectively) and lower RMSD values compared to the synthetic bovine PPARγ agonist, 2,4-Thiazolidinedione (-4.12 kcal/mol), indicating a strong potential for modulating the receptor. Molecular dynamics simulations (MDS) further affirmed the stability of these polyphenols-bovine PPARγ complexes, suggesting their effective and sustained interactions. These polyphenols, known as fatty acid synthase inhibitors, are suggested to influence lipid metabolism pathways crucial to milk fat production, possibly through the downregulation of the MAPK pathway. The screened compounds showed favorable pharmacokinetic profiles, including non-toxicity, carcinogenicity, and high gastrointestinal absorption, positioning them as viable candidates for enhancing dairy cattle health and milk production. These findings may open new possibilities for the use of phytochemicals as feed additives in dairy animals, suggesting a novel approach to improve milk fat synthesis through the dual modulation of bovine PPARγ and MAPK pathways.

Exploring Natural Compounds as Potential CDK4 Inhibitors for Therapeutic Intervention in Neurodegenerative Diseases through Computational Analysis.

CDK4 is a member of the serine-threonine kinase family, which has been found to be overexpressed in a plethora of studies related to neurodegenerative diseases. CDK4 is one of the most validated therapeutic targets for neurodegenerative diseases. Hence, the discovery of potent inhibitors of CDK4 is a promising candidate in the drug discovery field. Firstly, the reference drug Palbociclib was identified from the available literature as a potential candidate against target CDK4. In the present study, the Collection of Open Natural Products (COCONUT) database was accessed for determining potential CDK4 inhibitors using computational approaches based on the Tanimoto algorithm for similarity with the target drug, i.e., Palbociclib. The potential candidates were analyzed using SWISSADME, and the best candidates were filtered based on Lipinski's Rule of 5, Brenk, blood-brain barrier permeability, and Pains parameter. Further, the molecular docking protocol was accessed for the filtered compounds to anticipate the CDK4-ligand binding score, which was validated by the fastDRH web-based server. Based on the best docking score so obtained, the best four natural compounds were chosen for further molecular dynamic simulation to assess their stability with CDK4. In this study, two natural products, with COCONUT Database compound ID-CNP0396493 and CNP0070947, have been identified as the most suitable candidates for neuroprotection.

GSK-3β and Non-Small Cell Lung Cancer: A Review of Its Role in Disease Mechanisms and Treatment Strategies

Introduction Recent molecular docking studies have identified potential inhibitors targeting GSK-3β, offering promising avenues for therapeutic intervention. These inhibitors could potentially disrupt the oncogenic signaling pathways mediated by GSK-3β, thereby halting or reversing tumor progression. This literature review seeks to deliver a thorough examination of the current knowledge regarding GSK-3β influence on NSCLC. Methods The author carried out an extensive literature review utilizing various electronic databases such as PubMed, Scopus, and Europe PMC. The search keywords included "GSK-3β," "glycogen synthase kinase-3 beta," "non-small cell lung cancer," "NSCLC," "prognosis," "apoptosis," "cell proliferation," "autophagy," "radiosensitivity," "tumor differentiation," and "molecular docking." The findings from the included studies were integrated into a narrative review, emphasizing GSK-3β role in NSCLC pathogenesis, its potential as a therapeutic target, and its utility as a prognostic biomarker. Results GSK-3β is a multifunctional serine/threonine kinase involved in various cellular processes, including proliferation, differentiation, motility, and survival. Its expression is associated with NSCLC differentiation, with GSK-3β-negative tumors showing better prognosis. Preclinical studies have identified potential GSK-3β inhibitors with favorable docking scores and ADME profiles for NSCLC treatment. However, targeting GSK-3β for NSCLC treatment faces several significant challenges. One major issue is the broad role of GSK-3β in various cellular processes, including metabolism and cell survival, which increases the risk of off-target effects and toxicity. Conclusions GSK-3β has emerged as a critical biomarker in NSCLC, exerting a significant impact on disease progression, treatment response, and prognosis.

Exploring dimethoxy naphthalenyl methoxyphenyl quinazolinyl amine as a PDE10A inhibitor: In-silico studies, synthesis and binding interactions with serum albumin

Phosphodiesterase 10A (PDE10A) inhibitors stand out as key players in the quest for effective treatments against neurological disorders. Among them, Papaverine has gained attention for its ability to activate striatal output, hinting at potential antipsychotic properties. A thorough computational analysis of 28 alkoxy quinazoline derivatives derived from Papaverine led to the discovery of Dimethoxynaphthalenyl methoxyphenyl quinazolinyl amine (QPhN), addressing its exceptional docking score (-27.71) and binding energy (−44 kJ/mol). The main contributors of this binding were Gln716 and Phe719. Absorption, Distribution, Metabolism, Excretion (ADME) and Toxicity analysis predicted its drug likeness, bioavailability and highest CNS scoring (0.0409). Notably, its synthesis involved two-step process, first cyclic addition of dimethoxy quinazolinyl chloride and dioxaborolanyl phenol took place along with alkylation with bromomethyl naphthalene. To better understand the ADME profile of QPhN, its interaction with serum albumin (SA) was analyzed with the help of Photo physical studies. Fluorescence emission of SA was quenched to reveal the subtle shifts (distinct red shift of around 20 nm) in the protein’s microenvironment. Through static quenching analysis, a binding constant value in the range (K = 104 M−1) underscored the prevalence of non-covalent interactions between QPhN and SA with involvement of one binding site. Additionally, the interaction between QPhN and SA was enthalpically and entropically compelled to sub domain IIA with ΔH (−72.2 kJ/mol), ΔS (−210.37 J mol−1 K−1) and ΔG (−9.62 kJ/mol) values. The binding represents weak perturbation (1–3 %) of α-helix content of SA with increasing concentration of QPhN. The study highlighted the importance of QPhN as a promising marker for PDE10A.

Evaluation of 3, 3’-Disubstituted Oxindoles Derivatives as a Potential Anti- Cancer Tyrosine Kinase Inhibitors-molecular Docking and ADME Studies

Aim: This study aims to explore the binding interactions between synthesized 3,3’-Disubstituted Oxindoles and the HCK enzyme, with the specific goal of discovering potential anticancer agents. Background: Cancer presents an ongoing global health challenge, necessitating the exploration of innovative therapeutic approaches. Isatin derivatives and pyridine compounds hold great promise for the development of anticancer drugs due to their wide-ranging biological activities. Moreover, HCK plays a significant role in chemotherapy resistance and reduced drug efficacy in clinical settings, highlighting its importance in the intricate network of cancer pathophysiology. There is an urgent need for targeted interventions to regulate HCK activity and enhance cancer treatment outcomes. Methods: In our study, we ensured meticulous optimization of protein and ligand preparation to guarantee accurate docking simulations. We conducted molecular docking analyses using the state-of-the-art Glide module and assessed ADME properties using the Schrödinger suite's QikProp tool. Results: Through molecular docking, compounds 3c and 3e have emerged as promising anticancer agents with low docking scores against Tyrosine Kinase. Further ADME analysis has provided valuable insights into the compounds' in-silico behaviour, while computed dipole moments have enhanced our understanding of their physicochemical characteristics Conclusion: In this study, we explored how the synthesized compounds bind within the HCK active site, indicating potential anticancer properties. Through in silico docking, we identified compounds 3c and 3e as possible anticancer agents, with the lowest docking scores of -7.621 and -7.602 kcal/mol against Tyrosine Kinase. These findings emphasize the importance of computational approaches in drug discovery and offer valuable insights for future research and development efforts.

Synthesis and anticancer evaluation of diaryl pyrido[2,3-d]pyrimidine /alkyl substituted pyrido[2,3-d]pyrimidine derivatives as thymidylate synthase inhibitors

Worldwide, colorectal cancer (CRC) is the third most common type of cancer and the second most common cause of cancer-related deaths. Thymidylate synthase (TS) is a crucial component of DNA biosynthesis and has drawn interest as an essential target for cancer treatment. In the current work, we have designed and synthesized twenty-eight new diaryl-based pyrido[2,3-d]pyrimidine/alkyl-substituted pyrido[2,3-d]pyrimidine derivatives and evaluated their anticancer activity against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines cell lines. Additionally, we have carried out TS inhibitory activity and in silico studies for compounds 1n and 2j. All the synthesized compounds exhibited good anticancer activity, but among them, compounds 1n and 2j showed excellent anticancer activity, having IC50 values of 1.98 ± 0.69, 2.18 ± 0.93, 4.04 ± 1.06, and 4.18 ± 1.87 µM; and 1.48 ± 0.86, 3.18 ± 0.79, 3.44 ± 1.51, and 5.18 ± 1.85 µM, against the HCT 116, MCF-7, Hep G2, and PC-3 cell lines respectively with control raltitrexed (IC50 1.07 ± 1.08, 1.98 ± 0.72, 1.34 ± 1.0, and 3.09 ± 0.96 µM, respectively) and hTS inhibitory activity with IC50 values of 20.47 ± 1.09 and 13.48 ± 0.96 nM with control raltitrexed (IC50 14.95 ± 1.01 nM). Further, the mechanism of inhibition was revealed by molecular docking, which showed the binding pattern of 1n and 2j to the catalytic site of TS with docking scores of -10.6 and − 9.5 kcal/mol, respectively, with reference raltitrexed (-9.4 kcal/mol). Additionally, the assessment of physicochemical, biochemical, structural, and toxicological characteristics were also in the acceptable range for these compounds. Based on the anticancer activity of compounds, SAR was also performed for lead optimization.

Insights Into Benzothiazolyl‐Coupled Azetidinone Moieties Toward EGFR Binding and Stability Analysis—Evidence From Molecular Docking and Dynamics Simulation

ABSTRACTBreast cancer, a formidable threat to women's health, mainly manifests in the HER2 subtype, affecting approximately one in five women. Thus, this study endeavors to pioneer novel approaches by exploring the efficacy of benzothiazole‐coupled azetidinone derivatives against EGFR. We aimed to elucidate their potential by employing a comprehensive array of in silico methodologies, including molecular docking, pharmacokinetics profiling, pharmacophore mapping, molecular dynamic simulations, and MMPBSA analysis. Remarkably, our results demonstrate that our designed molecules adhere to Lipinski's rule and comply with essential physiochemical and druggable properties, affirming the promise of these compounds. Ligand MS60 emerges as a lead, showcasing the most substantial interaction with the EGFR receptor, underscored by its impressive docking score of −8.199 kcal/mol. Furthermore, molecular dynamics simulations conducted via GROMACS corroborate the stability of the MS60‐EGFR complex, portraying minimal fluctuations. This assertion is further validated through MMPBSA, PCA analysis, DCCM, and FEL studies, underscoring the robustness of our findings. We have designed the pharmacophore model to unravel critical steric and electronic attributes essential for effective supramolecular interactions with the EGFR receptor. Notably, the presence of the R10, R11, and A4 groups within the ligands underscores their pivotal role in eliciting pharmacological activity, offering valuable insights for further exploration and development.

Sedative and anxiolytic effects of Capparis sicula Duhamel: in vivo and in silico approaches with phytochemical profiling.

The World Health Organization reports that 30% of adults worldwide suffer from insomnia, while 10% of people worldwide suffer with various forms of anxiety. The significant negative effects of conventional medications used to treat anxiety and insomnia, such as abuse, addiction, amnesia, and cognitive and sexual dysfunction, have led to an increased preference for naturally derived substances with fewer side effects. Accordingly, in this study, the sedative and anxiolytic effects of n-hexane, ethyl acetate (EtOAc), methanol (MeOH) and water extracts of the aerial parts of Capparis sicula Duhamel., which is used for sedative purposes in folk medicine, were evaluated. To evaluate the sedative and anxiolytic effects of each extract, bioassay systems were used including traction and hole-board tests. The MeOH extract of C. sicula was the most active extract on in vivo traction and hole-board tests compared to Diazepam. From the MeOH extract, major components were isolated, and their structures were identified as three flavonoid glycosides [rutin (1), quercetin-3-O-glucoside (2), and quercetin 3-O-rhamnoside (3)] using spectral techniques. The most abundant component was determined to be rutin, comprising 8mg/100mg dry extract in MeOH extract and 76.7mg/100mg dry fraction in fraction C using HPLC. The molecular docking studies evaluated the interaction of isolated flavonoid glycosides with the interaction energies and protein-ligand interaction details of the anxiety-related receptors GABAA and GABAB. For the GABAA receptor, quercetin-3-O-glucoside demonstrated the highest docking score. Quercetin-3-O-rhamnoside and rutin also show promising interactions, particularly with the GABAB receptor, highlighting their potential as modulators of these receptors. In conclusion, the use of C. sicula for sedative purposes in folk medicine has been confirmed for the first time by in vivo studies, and its possible active compounds and sedative-anxiolytic mechanism have been determined through phytochemical and in silico studies.

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates.

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