Docking Score Research Articles

Acetylcholine and butyrylcholine esterase inhibitory potential of newly synthesized halogenated compounds: In vitro, in silico and MD simulation

Schiff bases have numerous applications especially in the medicinal chemistry. Keeping in view their importance, two new compounds; (E)-2-(((4‑bromo-2-(trifluoromethyl) phenyl)imino)methyl)-4-nitrophenol (1) and (E)-3-((4‑bromo-2-(trifluoromethyl)phenylimino) methyl)pyridin-2-amine (2) have been synthesized. These Schiff bases were characterized with modern spectral tools while precise structures were confirmed through XRD which revealed that compound 1 was monoclinic and compound 2 was orthorhombic. The synthesized compounds were further evaluated theoretically by applying density functional theory approach. Regression coefficient (R2) was utilized to compare the different parameters between DFT and XRD data. Hirshfeld surface study was used to find out the different interactions between the atoms presented in the crystalline molecules. Online free tool was used against AChE and BChE for accomplishment of the molecular modeling study. The molecular dynamics simulation study was also conducted to check the binding mechanism of the most active compound on AChE. On the basis of the docking score and MD simulation, compound 1 depicted more inhibition potential. The in-vitro studies further confirmed that synthesized Schiff bases have potential to cure the Alzheimer disease by inhibiting enzymes related to this disease.

Compounds Derived from 5-Fluoropyridine and Benzo[b]thiophene: Killing Mycobacterium tuberculosis and Reducing its Virulence.

The rise of drug-resistant Mycobacterium tuberculosis (Mtb) has extended the duration of tuberculosis (TB) treatment and reduced the likelihood of cure. One strategy to combat this issue is the development of inhibitors targeting the virulence factors of bacterial pathogens. Mtb' catalase (KatG) is crucial for its detoxification mechanisms and also serves as a significant virulence factor for the bacterium. In this study, twelve derivatives synthesized from 5-fluoropyridine and benzo[b]thiophene demonstrated antimycobacterial efficacy with minimum inhibitory concentrations (MICs) varying between 0.5 and 32 μg/mL. Compound 2, 1-(benzo[b]thiophen-2-ylmethylene) thiosemicarbazide, emerged as the most potent candidate. It effectively inhibited Mtb KatG, enhanced the production of reactive oxygen species (ROS) in Mtb, and achieved Mtb killing within 96 hours at a concentration of 2 μg/mL (4×MIC). Molecular docking simulations revealed that compound 2 binds tightly to the active site of Mtb-KatG with a docking score of 114, indicating that it may serve as a potent inhibitor of Mtb-KatG. The rabbit skin tuberculosis model was employed to assess the virulence of Mtb. Animal study results indicated that the granulomas induced by Mtb after treatment with compound 2 were reduced in size, exhibited a lower bacterial load, and the bacteria were no longer aggregated, in contrast to those caused by untreated Mtb. Hence, compound 2 can be regarded as a molecule capable of neutralizing the virulence factors of Mtb. This research offers insights into the design of anti-Mtb molecules with novel mechanisms of action.

Phytochemicals of Different Medicinal Herbs as Potential Inhibitors Against Dengue Serotype 2 Virus: A Computational Approach.

Dengue is one of the major mosquito-borne infectious diseases of the present century, reported to affect about 100-400 million people globally. The lack of effective therapeutic options has inspired several in vitro and in silico studies for the search of antivirals. Our previous study revealed the anti-dengue activity of different plant extracts from Plumeria alba, Bacopa monnieri, Vitex negundo, and Ancistrocladus heyneanus. Therefore, the current in silico study was designed to identify the phytochemicals present in the aforementioned plants, which are possibly responsible for the anti-dengue activity. Different plant databases as well as relevant literature were explored to find out the major compounds present in the above-stated plants followed by screening of the retrieved phytochemicals for the assessment of their binding affinity against different dengue viral proteins via molecular docking. The best poses of protein-ligand complexes obtained after molecular docking were selected for the calculation of binding free energy via MM-GBSA method. Based on the highest docking score and binding energy, six complexes were considered for further analysis. To analyze the stability of the complex, 100ns molecular dynamics (MD) simulations were carried out using Desmond module in the Schrodinger suite. The MD simulation analysis showed that four compounds viz. liriodendrin, bacopaside VII, isoorientin, and cynaroside exhibited stability with viral targets including the RdRp, NS3 helicase, and E protein indicating their potential as novel anti-dengue antivirals.

Identification of different extracts and phytoconstituents of Callistemon viminalis Cheel for their anti-anxiety effects based on pharmacognostic, toxicological, and pharmacological strategies

BackgroundPsychiatric disorders like depression and anxiety are global challenges, exacerbated by the limitations of synthetic medications, including addiction and toxic side effects. MethodsThis study meticulously investigated the pharmacognostic, phytochemical, toxicological, and pharmacological properties of Callistemon viminalis Cheel. Toxicological assessments, including hemocompatibility assays, LD50 studies, FOB analysis, biochemical parameters, and structural integrity of vital organs, were conducted on aqueous, methanolic, chloroform, and petroleum ether extracts of leaves and stems. Phytochemical profiling via qualitative tests and GC-MS screened extracts for molecular docking against key receptors. Categorically screened extracts were evaluated for therapeutic potential against LPS-induced anxiety in mice. ResultsToxicological evaluations on experimental animals demonstrated the safety of various extracts, evidenced by no in vitro and in vivo toxicity. GC-MS identified numerous phytochemicals that passed “Lipinski's Rule of Five.” These compounds were screened for molecular docking, revealing significant binding affinities with CB1, SERT, α2A-AR, and GABAβ2 receptors, suggesting potential therapeutic effects against anxiety. The phytoconstituents with the highest docking scores, particularly in aqueous and methanolic extracts, were further validated for their therapeutic efficacy. Preliminary analysis based on the EPM test and serum cortisol levels confirmed these extracts' superior therapeutic effectiveness. ConclusionIn conclusion, aqueous and methanolic extracts of Callistemon viminalis Cheel’s leaf and stem showed promising potential as therapeutic interventions for anxiety disorders.

Interactions of Potential Endocrine-Disrupting Chemicals with Whole Human Proteome Predicted by AlphaFold2 Using an In Silico Approach.

Binding with proteins is a critical molecular initiating event through which environmental pollutants exert toxic effects in humans. Previous studies have been limited by the availability of three-dimensional (3D) protein structures and have focused on only a small set of environmental contaminants. Using the highly accurate 3D protein structure predicted by AlphaFold2, this study explored over 60 million interactions obtained through molecular docking between 20,503 human proteins and 1251 potential endocrine-disrupting chemicals. A total of 66,613,773 docking results were obtained, 1.2% of which were considered to be high binding, as their docking scores were lower than -7. Monocyte to macrophage differentiation factor 2 (MMD2) was predicted to interact with the highest number of environmental pollutants (526), with polychlorinated biphenyls and polychlorinated dibenzofurans accounting for a significant proportion. Dimension reduction and clustering analysis revealed distinct protein profiles characterized by high binding affinities for perfluoroalkyl and polyfluoroalkyl substances (PFAS), phthalate-like chemicals, and other pollutants, consistent with their uniquely enriched pathways. Further structural analysis indicated that binding pockets with a high proportion of charged amino acid residues, relatively low α-helix content, and high β-sheet content were more likely to bind to PFAS than others. This study provides insights into the toxicity pathways of various pollutants impacting human health and offers novel perspectives for the establishment and expansion of adverse outcome pathway-based models.

Molecular Modeling Studies of Similar Molecules to Selective Estrogen Receptor Degrader Elacestrant as Inhibitors of SARS-COV-2.

Coronavirus 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) strain. Many anticancer compounds have been repurposed as effective anti-coronavirus agents and are currently in a clinical trial to be evaluated for treatment. Elacestrant is a novel selective estrogen receptor degrader (SERD). A fingerprint Tanimoto-based 2-dimensional similarity search was performed in the PubChem database using elacestrant as a prototype. The chemical compounds were downloaded, and virtual screening, molecular docking, and molecular dynamics were further used to identify the most active molecules in the binding pocket SARS-COV-2 main protease. Eight compounds with superior docking score, gscore, and glide binding energy were identified. Molecular dynamic simulations (MD) were performed at 100 ns to remove the false interactions between the receptor and the active ligands. The results showed that all the compounds displayed good stability. Further, the ADMET results showed that compounds CID58023104 was observed to be deemed a hit compound; hence, CID58023104 and could be optimize, derivatize, and explore for further development as an anti-coronavirus agent targeting SARS-COV-2 main protease.

Phytochemical screening, molecular docking, antifertility investigations, and ADME potential of various extracts of Pandanus odoratissimus leaves.

The purpose of this study was to explore the molecular docking characteristics and antifertility impacts of petroleum ether extract (PEEPO) and chloroform (CHEPO) derived from Pandanus odoratissimus (PO) leaves. TriposSybyl-X 2.1 for molecular docking and Swiss ADME for ADME predictions were used. Antifertility activity was determined by using two invivo animal models, with a focus on estrogenic/antiestrogenic activity and anti-implantation effects. The findings showed that at different doses (100, 200, and 400 mg/kg), PEEPO had more anti-implantation effect than CHEPO. After taking either extract orally for up to 4,000 mg/kg, no acute toxicity was found. Furthermore, both extracts substantially raised blood oestrogen levels while lowering serum cholesterol and LDL levels, improving their antiimplantation and estrogenic activities, whether given alone or in combination with ethinyl estradiol. Molecular docking scores suggested strong interactions between phytochemicals in the extracts and estrogen receptors. ADME studies highlighted four phytochemicals present in PO leaves, showing high gastrointestinal absorption, blood-brain barrier permeability, and negative Log Kp values, indicating their potential as antifertility agents. The phytochemicals in both PEEPO and CHEPO demonstrated promising antifertility potential and interactions with estrogen receptors. Isolation of these phytochemicals could lead to the development of effective herbal antifertility formulations.

Synthesis and In Silico Evaluation of Piperazine-Substituted 2,3-Dichloro-5,8-dihydroxy-1,4-naphthoquinone Derivatives as Potential PARP-1 Inhibitors.

PARP-1 (poly(ADP-ribose)-polymerase 1) inhibitors are vital in synthetic lethality, primarily due to their specificity for PARP-1 over PARP-2 (PARP-1 > PARP-2). This specificity is crucial as it allows precise inhibition of PARP-1 in tumor cells with Breast Cancer 1 protein (BRCA1) or BRCA2 deficiencies. The development of highly specific PARP-1 inhibitors not only meets the therapeutic needs of tumor treatment but also has the potential to minimize the adverse effects associated with nonselective PARP-2 inhibition. In this study, a series of novel 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (DDNO) derivatives were synthesized, characterized, and evaluated regarding their PARP-1 inhibitory and cytotoxic activity. Compound 3 exhibited the highest cytotoxic potential against all cell lines, except for MDA-MB-231 cells. The inhibitory potential of these molecules against PARP-1 was evaluated through in silico molecular docking and molecular dynamics studies. Notably, compounds 5, 9, and 13 exhibited significant inhibitory activity in silico results, interacting with critical amino acids known to be important for PARP-1 inhibition during simulations. These compounds exhibited target-specific and strong binding profiles, with docking scores of -7.17, -7.41, and -7.37 kcal/mol, respectively, and MM/GBSA scores of -52.51, -43.77, and -62.87 kcal/mol, respectively. These novel compounds (DDNO derivatives) hold promise as potential PARP-1 inhibitors for the development of targeted therapeutics against cancer.

Insight into the Binding Interaction Mechanism of the Ligand M1069 with Human Serum Albumin and A2A Adenosine Receptor—A Biophysical Approach

The study focuses on M1069, a promising drug for solid tumors functioning as an A2A adenosine receptor antagonist. Herein, we investigate the binding mechanism of the drug molecule M1069 by employing computational techniques to draw comparisons with Human serum albumin (HSA), shedding light on the intricate interactions between M1069 and its target as well. The molecular docking results suggest that the drug molecule binds very well with the HSA protein when compared to A2AAR with the docking score of −7.02 kcal/mol. To substantiate the molecular interactions between the drug and the protein structure, comprehensive molecular dynamic simulations were performed for a period of 100 ns. This approach facilitated an in-depth analysis of the dynamic relationships and behaviors between the drug and the protein, offering valuable insights into their intermolecular dynamics and stability. Subsequently, DFT analysis is conducted to assess the inhibitory efficacy of the drug, employing the B3LYP technique. Additionally, an investigation into the pharmacological ADMET parameters of the drug molecule resulted in gastrointestinal absorption. These outcomes contribute to a better understanding of the interaction dynamics between the drug and the proteins, providing valuable insights that can enhance the drug discovery process.

Anti- COVID-19 drug discovery by flavonoid derivatives: an extensive computational drug design approach.

The present study deals with the in-silico analyses of several flavonoid derivatives to explore COVID-19 through pharmacophore modelling, molecular docking, molecular dynamics, drug-likeness, and ADME properties. The initial literature study revealed that many flavonoids, including luteolin, quercetin, kaempferol, and baicalin may be useful against SARS β-coronaviruses, prompting the selection of their potential derivatives to investigate their abilities as inhibitors of COVID-19. The findings were streamlined using in silico molecular docking, which revealed promising energy-binding interactions between all flavonoid derivatives and the targeted protein. Notably, compounds 8, 9, 13, and 15 demonstrated higher potency against the coronavirus Mpro protein (PDB ID 6M2N). Compound 8 has a -7.2 Kcal/mol affinity for the protein and binds to it by hydrogen bonding with Gln192 and π-sulfur bonding with Met-165. Compound 9 exhibited a significant interaction with the main protease, demonstrating an affinity of -7.9 kcal/mol. Gln-192, Glu-189, Pro-168, and His-41 were the principle amino acid residues involved in this interaction. The docking score for compound 13 is -7.5 Kcal/mol, and it binds to the protease enzyme by making interactions with Leu-41, π-sigma, and Gln-189. These interactions include hydrogen bonding and π-sulfur. The major protease and compound 15 were found to bind with a favourable affinity of -6.8 Kcal/mol. This finding was further validated through molecular dynamic simulation for 1ns, analysing parameters such as RMSD, RMSF, and RoG profiles. The RoG values for all four of the compounds varied significantly (35.2-36.4). The results demonstrated the stability of the selected compounds during the simulation. After passing the stability testing, the compounds underwent screening for ADME and drug-likeness properties, fulfilling all the necessary criteria. The findings of the study may support further efforts for the discovery and development of safe drugs to treat COVID-19.

Unveiling the bioactive potential of organotin(IV) complexes of hydrazones: Synthesis, spectral characterization, in vitro and in silico exploration

In the quest of compounds with potent antimicrobial and antioxidant properties, we conducted a comprehensive investigation involving four hydrazone ligands [H2L1–4] (1–4) and their respective sixteen organotin(IV) complexes (5–20) with general formula R″2SnL1–4 [R″ = Me, Et, Bu, Ph]. Various spectroscopic and physicochemical studies were employed for the thorough characterization of the synthesized compounds, which demonstrated the tridentate chelation of ligands via ONO donor domains by Ophenolic, Nazomethine and Oenolic atoms displaying pentacoordinated geometry. Further, the compounds were subjected to bioactivity assays by targeting their in vitro antioxidant and antimicrobial studies. Complex 8 [Ph2SnL1], 12 [Ph2SnL2], 16 [Ph2SnL3], 19 [Bu2SnL4] and 20 [Ph2SnL4] emerged as particularly noteworthy antimicrobials, exhibiting a higher level of inhibition having minimum inhibition concentration (MIC) value in the range of 0.0042–0.0095 µmol/mL. Among them, complex 20 exhibited superior activity with MIC values of 0.0042 µmol/mL against C. albicans and S. aureus, surpassing the standard drugs ciprofloxacin (0.0047 µmol/mL) and fluconazole (0.0051 µmol/mL). Additionally, all the compounds showed notable radical scavenging activity, and the activity of complexes increases in the order Ph2SnL1−4 (1.93–3.68 µM) > Bu2SnL1−4 (2.26–4.15 µM) > Et2SnL1−4 (2.91–4.97 µM) > Me2SnL1−4 (3.49–5.10 µM) (DPPH assay). Furthermore, In silico studies including Molecular docking, Density Functional Theory (DFT), Molecular Electrostatic Potential (MESP), Absorption, Distribution, Metabolism, Excretion and Toxicity ADMET) analysis highlighted the significance of highly potent antimicrobial compounds (4, 17–20) as potential drug candidates. Each compound exhibited binding affinity with protein binding site, including carbon-hydrogen bonds, conventional hydrogen bonds, alkyl interactions and pi-alkyl interactions. Compound 20 exhibited a superior docking score of −137.644 kcal/mol at the active site of C. albicans (PDB ID: 4HOE). The binding energy of the compounds followed the order: 20 (−11.6577 eV) < 19 (−11.3193 eV) < 18 (−9.23989 eV) < 17 (−8.23386 eV) < 4 (−7.01131 eV) and coincided well with the findings of experimental research. In summary, this comprehensive research underscores the substantial biological activity of the synthesized compounds and their promising potential for future applications in drug development.

Targeting LIMK1 in Alzheimer's Disease: A Multifaceted Computational Investigation Involving ADMET, Virtual Screening, Molecular Docking, and Molecular Dynamics

LIM domain kinases (LIMKs), which include LIMK1 and LIMK2, are key proteins in actin dynamics. On this basis, the inhibition of LIMK1 enhances dendritic spine density and size in dementia, reducing Alzheimer's disease (AD) effects. Therefore, several small molecules were discovered as potential therapeutic targets for AD. Herein, a pharmacophore-based virtual screening was employed to identify novel potential LIMK1 inhibitors. The pharmacophore model derived from the co-crystallized receptor structure of PubChem-329823760: LIMK1 (PDB ID: 5NXC) was then used for virtual screening. After applying Lipinski's rules and pharmacophore filters, 29 potential hits were identified. Molecular docking simulations were performed to determine the binding affinities of these candidates against LIMK1, with results ranging from -5.20 to -10.60 kcal/mol. Notably, PubChem-136621040 showed the highest binding affinity against the target protein, with a docking score of -10.60 kcal/mol, slightly surpassing the native ligand, PubChem-329823760, possessing a lower docking score of -9.80 kcal/mol. The drug-likeness and toxicity properties of target compounds were assessed through ADMET evaluations. A series of 75 nanosecond molecular dynamics (MD) simulations were conducted on the complexes generated by the best-docked molecule and the native ligand. RMSD, RMSF, SASA, and Rg calculations of their trajectories were also calculated. PubChem-136621040 possessed an average RMSD value of 0.23 nm, lower than the native ligand's 0.31 nm, indicating a greater binding stability. The RMSF results also revealed that the best-docked compound had a lower value (0.10 nm), while the native ligand possessed a value of 0.12 nm. The SASA values for both the native ligand and the best-docked compound were nearly identical, at 150.20 nm2 and 150.80 nm2, respectively. The Rg results demonstrated that both complexes maintained their rigidity throughout the simulation, with similar average values of 2.04 nm for the native ligand and 2.06 nm for the best-docked compound.

Exploring Radioiodinated Anastrozole and Epirubicin as AKT1-Targeted Radiopharmaceuticals in Breast Cancer: In Silico Analysis and Potential Therapeutic Effect with Functional Nuclear Imagining Implications.

This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.

Identification of potential NUDT5 inhibitors from marine bacterial natural compounds via molecular dynamics and free energy landscape analysis.

NUDIX hydrolase 5 (NUDT5) is an enzyme involved in the hydrolysis of nucleoside diphosphates linked to other moieties, such as ADP-ribose. This cofactor is vital in redox reactions and is essential for the activity of sirtuins and poly(ADP-ribose) polymerases, which are involved in DNA repair and genomic stability. It has been shown that NUDT5 activity can also influence NAD+ homeostasis, thereby affecting cancer cell metabolism and survival. In this regard, the discovery of NUDT5 inhibitors has emerged as a potential therapeutic approach in cancer treatment. In this study, we conducted a high-throughput virtual screening of marine bacterial compounds against the NUDT5 enzyme and four molecules were selected based on their docking scores. These compounds established strong interactions within the NUDT5 active site, with molecular analysis highlighting the key role of Trp28A and Trp46B residues. Molecular dynamics simulations over 200 ns indicated a stable behavior, in association with root mean square deviation values always below 3 Å, suggesting conformational stability. Free energy landscape analysis further supported their potential as NUDT5 inhibitors, offering avenues for novel therapeutic strategies against NUDT5-associated breast cancer.

Integrating computational 3D-QSAR and pharmacophore modelling in diverse natural phytochemicals library for targeted therapy against breast cancer estrogen receptors

Breast cancer stands as a pervasive global health challenge, profoundly impacting the physical and emotional well-being of individuals. The relentless growth of malignant cells within breast tissues necessitates comprehensive research into the disease's origin, early detection, and treatment strategies. This study focused on constructing pharmacophores and 3D-QSAR models to dissect the crucial structure attributes essential for inhibiting Estrogen receptors. By employing ligand-based pharmacophore modeling and Atom-based-3D-QSAR techniques within the Schrödinger Phase module, we analyzed the inhibitory activity of 202 natural compounds and Tamoxifen as the control drug. To identify promising candidates, five molecules (Genistein, Coumestrol, Apigenin, Emodin, and Daidzein) were strategically chosen based on prediction from the 3D-QSAR pharmacophore model. These molecules are further assessed through model validation and virtual screening. The generated pharmacophore model (ADHR.10) reveals key features like hydrogen bond donors (HBD), hydrogen bond acceptors (HBA), and hydrophobic interactions. The resulting 3D-QSAR model predicted and stability was validated through the Xternal validation plus tool. The ADHR.10 model guided the systematic screening of natural compounds, resulting in the identification of the top five hits with promising pharmacological activity. Molecular docking scores demonstrated the compound's binding affinity with ESR1 (PDB ID: 6PSJ) and ESR2 (PDB ID: 1QKM). One standout compound, Coumestrol, displayed an exceptional binding affinity with ESR2 outperforming Tamoxifen. The top compounds exhibited both strong binding and stability, making them a promising candidate. Furthermore, Molecular Dynamics Simulation (MDS) demonstrated Coumestrol's superior stability compared to the control drug against the ESR1 and ERS2 proteins. Coumestrol exhibits lower average fluctuation in RMSD and residue-specific dynamics (RMSF) indicating stability than control. Specifically, designed compounds, rooted in natural sources, demonstrated excellent potential as breast cancer treatment candidates. These findings highlight them as promising lead candidates for the development of targeted breast cancer therapies and emphasize the potential of computational approaches in discovering new therapeutic avenues.

Antiproliferative Impact of Linagliptin on the Cervical Cancer Cell Line.

This study aimed to assess linagliptin's inhibitory effects on the proliferation of cervical cancer cell lines and investigate its potential for targeting human heat shock protein 90. Linagliptin's cytotoxicity was assessed on a cervical cancer cell line (Hela cancer cell line) at two different incubation periods, 24 and 72 hours. The molecular docking between linagliptin and the receptor protein human Hsp 90 (PDB code: 5XRE) was performed using the Biovia Discovery Studio and AutoDock tool software. The Discovery Studio visualizer generated three-dimensional (3D) and two-dimensional (2D) interactive images. The study's cytotoxicity results demonstrated that linagliptin can inhibit the proliferation of cervical cancer cells. The cytotoxicity exhibited a time-dependent pattern (cell cycle specific). The molecular docking study was conducted to investigate the interaction between linagliptin and human Hsp90. The study identified 11 sites where linagliptin can bind to Hsp90 amino acid residues. The total docking score for this interaction was -10.3 kcal/mol. The most potent binding occurred through conventional hydrogen bonds with the ASP:54 amino acid residues at a distance of 2.93 Å. The docking scores for linagliptin were comparable to those of the reference drug geldanamycin, indicating a strong interaction between linagliptin and Hsp90. The study has found that linagliptin successfully reduces the growth of cervical cancer cells with a time-dependent cytotoxic pattern. The potential anticancer mechanism of linagliptin can be inferred by analyzing the docking score and docking pattern between linagliptin and Hsp90, suggesting that linagliptin targets human Hsp 90.

In silico Design of a Quadruplex RNA Aptamer Against Carcinoembryonic Antigen, and Evaluating its Potential as a Drug Delivery Vehicle

Background: Colorectal cancer is the third most common cancer worldwide, with carcinoembryonic antigen (CEA) being a key biomarker for tumor prognostic assessment. This study focused on the in silico development of an RNA aptamer capable of efficiently targeting the CEA biomarker, and evaluating its potential to act as a drug delivery vehicle of chemotherapeutic anticancer drugs. Methods: In this study, five G-quadruplex RNA aptamers were manually designed and docked with the CEA protein. The aptamer sequence with the best docking score was optimized through various mutations, and these mutant sequences underwent drug-aptamer docking using AutoDock vina, followed by further docking experiments with CEA, with and without the drug, using the Hdock server. The best aptamer-drug configuration and the entire (aptamers-drug)-CEA complex were then analyzed using molecular dynamics (MD) simulation. Results: Irinotecan exhibited the highest binding affinity with three mutant sequences compared to 5-FU and Raltitrexed, with the seq 3-5/Irinotecan complex showing the best configuration (score: -11.6). This complex also demonstrated a good binding affinity with the target CEA (HDOCK score: -393.07). Throughout 31.6 ns simulation, the RMSD plot of the (aptamer-drug)-CEA complex showed an average of 8.7 A°. The residues of interacting amino acids had lower RMSF than 1.4 Å, except for the ALA A0 (RMSF:1.74 Å). Rg plot showed minimal fluctuation, which were maintained between 19.2 Å and 20.2 Å. The mean SASA was in the range of 112.8–125.8 nm2. H-bonds were observed with an average of 7.3 hydrogen bonds. MD simulation results indicated that the (aptamers-drug)-CEA complex maintained a stable, low-flexibility, and relatively compact structure throughout the simulation. Conclusion: The study concludes that the designed quadruplex RNA aptamer can potentially target the CEA biomarker with good binding affinity and serves as an effective carrier for Irinotecan. However, in vitro and in vivo experiments are necessary for further validation.

Design, Molecular Docking and Molecular Dynamic Simulation of New Heterocyclic Derivatives as Potential Anticancer Agents

Background: Despite significant progress in the development of anticancer medications, obstacles such as drug resistance, poor efficacy, and excessive toxicity have significantly impacted the daily lives of cancer patients. Consequently, the search for highly selective, effective, and non-toxic molecules remains a major challenge for cancer researchers. Objective: To utilize a computer program for evaluating new benzothiophene derivatives to investigate how they influence the estrogen-related receptor-gamma (ERRγ) active sites as anticancer agents. Methods: The molecular docking method used the Cambridge Crystallographic Data Centre's (CCDC) Genetic Optimization for Ligand Docking (GOLD) tool. We used the Desmond modules of the Schrodinger 2023 to perform MDS on the derivative with the highest docking score. The Swiss ADME server then assessed our drugs' pharmacokinetic profile, which included how well they crossed the blood-brain barrier (BBB), bound to P-gp, and were bioavailable. Results: The compounds were docked with the ERRγ crystal structure (2GPV) to assess their binding affinity to active sites. One of them earned a high score (102.62), and six compounds had a higher binding energy than the gold standard medication, tamoxifen. The molecular dynamic simulation analysis found that compound 1 closely matched the ERRγ based on RMSD and RMSF data. After examining the ADME study of practically active substances, they follow Lipinski's laws and other pharmacokinetic features. Conclusions: These chemicals have the potential to act as precursors in the development of new anticancer medicines.

Synthesis, Antimicrobial Evaluation, Molecular Docking and Dynamics Simulations of Novel 2,3‐Disubstituted Quinazolin‐4(3H)‐one Derivatives

AbstractThe rise of multidrug‐resistant organisms (MDROs) represents a significant challenge to healthcare, underscoring the need for novel antimicrobial agents. Quinazolinone compounds, noted for their diverse biological activities, particularly at the 2nd and 3rd positions, in conjunction with sulphanilamide and isatin derivatives, present a promising avenue for antibacterial development. This study focuses on the synthesis of novel 2,3‐disubstituted quinazolin‐4(3H)‐one derivatives from Schiff base intermediates GA3A and GA3B. The synthesis involved the reaction of 2‐(substituted phenyl)‐4H‐benzo[d][1,3]‐oxazin‐4‐one with sulphanilamide, and the benzoxazinone intermediates were prepared by reacting anthranilic acid with benzoyl chloride. The antibacterial activities of the Schiff base intermediates and the final Mannich base compounds were evaluated against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa at concentrations of 50 µg/mL and 100 µg/mL using the agar well diffusion method, with Norfloxacin (50 µg/mL) as the reference standard. While all tested compounds exhibited lower antibacterial activity compared to the standard, GA4A1 showed enhanced efficacy against E. coli, achieving the highest docking score of 78.0352 against the E. coli protein (PDB ID: 1KZN). Molecular dynamics simulations revealed that the GA4A1‐E. coli complex stabilized after 40,000 ps, with root mean square deviation (RMSD) values ranging from 2.5 Å to 5 Å and low root mean square fluctuation (RMSF) values between 0.05 Å and 0.2 Å, indicating the stability of the complex. These findings underscore GA4A1’s potential as a potent antimicrobial agent against E. coli.

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 &amp;gt;3e &amp;gt;3d &amp;gt;3f &amp;gt;3b &amp;gt;3a.. KEYWORDS :Molecular docking, Molecular dynamic simulation, Molecular mechanics poisson-boltzmann surface area, Density functional theory, Anthelmintic activity.