Journal of Biomolecular Structure and Dynamics

Unveiling the potential of lichen compounds hyaluronic acid conjugates for cervical cancer treatment: a comprehensive in silico analysis

The current study investigated five lichen-derived compounds and their hyaluronic acid (HA) conjugates for activity against five key cervical cancer targets. The lichen compounds and the reference drug topotecan exhibited docking scores ranging from -5.5 to -10.1 kcal/mol and -6.4 to -8.5 kcal/mol, respectively. Notably, the HA-evernic acid conjugate demonstrated the strongest binding to BCL-2 (-10.1 kcal/mol), forming two hydrogen bonds (Ala97, Glu133) and four hydrophobic interactions (Asp100, Arg143, Val145, Tyr199). Similarly, the HA-salazinic acid conjugate displayed high affinity for histone deacetylase 6 (HDAC6; -9.9 kcal/mol). The top-performing compounds, fumarprotocetraric acid, salazinic acid, topotecan, and their HA conjugates, were advanced to computational validation. Pharmacokinetic analysis revealed that HA-salazinic acid (HA-SAL) possessed optimal ADMET properties, including 71.39% human intestinal absorption, no inhibition of cytochrome P450 enzymes or P-glycoprotein, and low toxicity in cardiac (hERG), hepatic, and aquatic models. Density functional theory (DFT) calculations highlighted the HA conjugates of fumarprotocetraric acid (HA-FUM) and salazinic acid as superior to topotecan, with HA-FUM showing the lowest energy gap (-0.1038 eV) and highest softness (19.2678 eV), indicative of enhanced reactivity. Molecular dynamics simulations further validated the stability of HA-salazinic acid-HDAC6 (PDB ID 3PHD) and HA-evernic acid-BCL-2 (PDB ID 4MAN) complexes, outperforming the standard drug hyaluronic acid conjugate. These results underscore the potential of lichen compound-HA conjugates, particularly fumarprotocetraric acid, salazinic acid, and evernic acid, as candidates for cervical cancer therapy. Further preclinical and clinical studies are warranted to evaluate their efficacy and safety for translational applications.

ZINC1797251, a novel natural product small molecule targets viral oncoprotein E6 in human papillomavirus-16 positive cervical cancer cells

Cervical cancer burden due to recurrent human papillomavirus (HPV) infections necessitates the urgent need to impede viral proliferation targeting the oncogene E6 of the high-risk serotype HPV16. This study aims to identify a small molecule from a natural product library that could prevent a tumorigenic complex of E6 with p53 in HPV16-positive cervical cancer cells.

Prognosis and immunotherapeutic implications of molecular classification of cervical cancer based on immunophenoscore-related genes

The immunophenoscore (IPS) is an important indicator for evaluating immunotherapy response. This work was designed to establish a prognostic model based on IPS-related genes in cervical cancer. Weighted correlation network analysis (WGCNA) was utilized to identify key modules related to IPS in cervical cancer data from The Cancer Genome Atlas (TCGA). The results show that the yellow module (158 genes) had a high correlation with both IPS_CTLA4_blocker and IPS_CTLA4_and PC1/PDL1/PDL2 blocker. Univariate cox regression analysis and LASSO regression analysis were performed based on 158 genes, and 9 characteristic genes were finally identified to construct the model. According to the differentially expressed genes, cervical cancer samples were divided into high-risk and low-risk groups and cluster 1.2.3. Higher risk scores associated with poorer prognosis. cluster2 and cluster3 were identified as cervical cancer subtypes with significant survival differences. cluster2 had higher immune cell infiltration levels and better prognosis, with greater sensitivity to Cyclopamine, Imatinib, MG-13, Paclitaxel, PHA-665752, Rapamycin, Sorafenib, Sunitinib, and VX-680. In contrast, cluster3 had higher TTN and PIK3CA mutations and greater sensitivity to AZ628, Dasatinib, Doxorubicin, HG-6-64-1, JQ12, Midostaurin, PF-562271, TAE684, and WH-4-023. In conclusion, we developed a feasible risk score model based on IPS-related genes for cervical cancer prognosis and identified potential drugs for different cervical cancer subtypes.

New sulfa drug derivatives and their zinc(II) complexes: synthesis, spectroscopic properties and in vitro cytotoxic activities

Synthesis of four sulfa drug derivatives (

Evaluation of anticancer activity of Gmelina asiatica leaves, in-vitro and in-silico studies

Cervical cancer poses a major threat to women's health worldwide, constituting the fourth most prevalent cancer among the female population. High-risk variants of human papillomavirus (HPV) with its oncogenic proteins are a necessary cause of cervical cancer. Due to the resistance of cancer cells to the current treatment, there is a need for new medicines with new strategies to treat cervical cancer.

Molecular insights of anticancer potential of usnic acid towards cervical cancer target proteins: An in silico validation for novel anti-cancer compound from lichens

Usnic acid is a marker compound produced from numerous lichens (symbiotic association of mycobiont and phycobiont) possessing higher bioavailability, potent and selective against cancer cells. Usnic acid is an underutilized and well-documented anti-cancer compound from lichens and its activity is not yet documented against cervical cancer. The main aim of the present research is to screen the anti-cancer potential of usnic acid against cervical cancer target proteins. The drug-likeness validation of usnic acid shows nil violations against all drug-likeness rules when compared with all three screened anti-cancer standard drugs and shows some violation in drug likeness prediction. Further, ADMET screening reveals usnic acids shows effective pharmacokinetic profiles with good bioactivity scores, essential for drug delivery and metabolism. DFT analysis of usnic acid reveals less energy gap (-0.1184), hardness (0.0592 eV), and high softness (16.8918 eV) scores against three anti-cancer drug DFT scores. Molecular docking study shows usnic acid possesses excellent binding affinity with all the nine screened cervical cancer target proteins with docking scores ranging from -6.9 to -9.1 kcal/mol. Three anti-cancer drugs showed docking scores with a range of -5.2 to -8.4 kcal/mol. Further, four top-scored complexes were taken for molecular dynamic simulation study reveal that usnic acid complexes (1KTZ-usnic acid and 2BIM-usnic acid) possess good simulation trajectories with cervical cancer target proteins than the selected anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Phytocompound identification of aqueous Zingiber officinale rhizome (ZOME) extract reveals antiproliferative and reactive oxygen species mediated apoptotic induction within cervical cancer cells: an in vitro and in silico approach

The prevalence of cervical cancer in women is in the fourth position among various other types of cancer globally. Many established therapies, including surgery, chemotherapy, and immunomodulation, are present, but high levels of side effects cause mortality and morbidity among the patients.

Exploring the interaction of Peloruside-A with drug resistant αβII and αβIII tubulin isotypes in human ovarian carcinoma using a molecular modeling approach

Microtubules (MTs) play an essential role in mitosis; hence they are identified as potential targets to design novel anti-mitotic agents. MT's are composed of α/β-tubulin isotypes that are associated with differential drug-resistant effects against MT-targeting agents. Peloruside-A (PLA) is a potent anti-mitotic agent showing excellent activity against taxol-resistant carcinoma. PLA alters MT dynamics by binding to the 'non-taxoid' site of β-tubulin. The abundance of βII and βIII tubulin isotypes in human ovarian carcinoma affects the efficacy of PLA. Nevertheless, the mechanism of PLA resistance due to βII and βIII tubulin isotype is not well understood. Therefore, we investigated the interactions of PLA with αβIIa, αβIIb, and αβIII tubulin isotypes which are predominantly expressed in the human ovarian carcinoma, using a molecular modeling approach. A sequence analysis study shows that the βIII isotype has seven residue variations at the 'non-taxoid' site compared to the βIIa and βIIb isotypes. Molecular docking and molecular dynamics simulation revealed that residue variation at the 'non-taxoid' site of βIII isotype affect PLA binding. Furthermore, binding energy calculations showed that αβIIa has the highest binding towards PLA, whereas αβIIb and αβIII isotypes shows weaker associations with PLA. Our computational study provides valuable structural and energetic information to increase understanding into the origin of PLA resistance in human ovarian carcinoma and could be helpful to develop potential PLA analogs against specific β-tubulin isotypes expressed in cancer cells.Communicated by Ramaswamy H. Sarma.

Structure-activity insights of harmine targeting DNA, ROS inducing cytotoxicity with PARP mediated apoptosis against cervical cancer, anti-biofilm formation and in vivo therapeutic study

Harmine exhibits pH dependent structural equilibrium and possesses numerous biological and pharmacological activities. Mode and mechanism of DNA binding and its cytotoxicity were studied by multiple spectroscopic, calorimetric, molecular docking and

Structural, vibrational, quantum chemical and thermal investigation of a nutraceutical drug in new zwitterionic cocrystal form (nicotinic acid: catechol) with enhanced cytotoxic activity in cervical cancer HeLa cell line

Nicotinic acid is an aphrodisiac, co-crystalized with catechol [NICCAT] in Zwitterionic structure used as unorthodox drugs. The present study, investigates its molecular structure, using X-ray diffraction and q chemical optimization technique. An examination of single-crystal XRD reported that crystal packing was highly stabilized with N.H···O and O-H···O. Hydrogen bond synthons. Besides, a weak C-H···O affinity was also contributed to the powerful molecular construction in crystal packing. To geometrically optimize the molecular structure, we employed the Density Functional Theory (DFT), by adopting the B3LYP function and Hartree-Fock (HF) level, with 6-311++G (d, p) a basic set. Moreover, spectral analyses were detected within an excitation range of 4000-400 cm

Synthesis, spectroscopic characterization, molecular docking and in vitro cytotoxicity investigations on 8-Amino-6-Methoxy Quinolinium Picrate: a novel breast cancer drug

Density Functional Theory (DFT) studies of the 8-Amino-6-Methoxy Quinolinium Picrate (8A6MQP) molecule have been carried out with extensive and accurate investigations of detailed vibrational and spectroscopic investigations as well as validated experimentally. The 8A6MQP sample was synthesized and characterized using FT-IR, FT-Raman, FT-NMR and UV-Vis spectroscopic techniques. Subsequently, the optimized molecular structure and harmonic resonance frequencies of the molecule were computed based on DFT/B3LYP method with a 6-311G++(d,p) basis set using the Gaussian 09 program. The experimental and calculated vibrational wavenumbers were assigned. The absorption spectrum of the molecule was computed in the liquid phase (ethanol), which exhibits n to л* electronic transition and compared with the observed UV-Vis spectrum. Frontier molecular orbital analysis shows the molecular reactivity and kinetic stability of the molecule. The Mulliken atomic charge distribution and molecular electrostatic potential surface analysis of the molecule validate the reactive site of the molecule. The natural bond orbital analysis proves the bioactivity of the molecule. Molecular docking analysis indicates that the 8A6MQP molecule inhibits the action of DNA topoisomerase 2-alpha protein, which is associated with breast cancer. In addition, the in vitro cytotoxicity analysis of the 8A6MQP molecule against human cervical cancer cell lines (ME180) and human breast cancer cell lines (MDA MB 231) were determined by MTT assay, which evidences that the title molecule exhibits higher inhibition against the breast cancer cell lines compared to that of cervical cancer cell lines. Hence, the present study paves the way for the development of novel drugs in the treatment of breast cancer.Communicated by Ramaswamy H. Sarma.

β-1,3-glucan from Euglena gracilis : a promising epidrug targeting epigenetic regulators PRMTs and SIRTs for therapeutic applications in ovarian cancer

Natural products serve as a valuable resource in drug discovery and the identification of bioactive molecules in the field of epimedicine, which targets epigenetic regulator enzymes through epidrugs. In this study, β-1,3-glucan (BG), a natural storage polysaccharide in

Evaluation of the efficacy of marine natural products against PARP-1/2 proteins in high-grade serous ovarian cancer: insights into MD and SMD simulations

High-grade serous ovarian cancer (HGSOC) is the most malignant and ubiquitous phenotype of epithelial ovarian cancer. Originating in the fallopian tubes and rapidly spreading to the ovaries, this highly heterogeneous disease is a result of serous tubal intraepithelial carcinoma. The proteins known as poly(ADP-ribose) polymerase (PARP) aid in the development of HGSOC by repairing the cancer cells that proliferate and spread metastatically. By using molecular docking to screen 1100 marine natural products (MNPs) from different marine environments against PARP-1/2 proteins, prominent PARP inhibitors (PARPi) were identified. Four compounds, alisiaquinone A, alisiaquinone C, ascomindone D and (+)-zampanolide referred to as MNP-1, MNP-2, MNP-3 and MNP-4, respectively, were chosen based on their binding affinity towards PARP-1/2 proteins, and their bioavailability and drug-like qualities were accessed using ADMET analysis. To investigate the structural stability and dynamics of these complexes, molecular dynamics simulations were performed for 200 ns. These results were compared with the complexes of olaparib (OLA), a PARPi that has been approved by the FDA for the treatment of advanced ovarian cancer. We determined that MNP-4 exhibited stronger binding energies with PARP-1/2 proteins than OLA by using MM/PBSA calculations. Hotspot residues from PARP-1 (E883, M890, Y896, D899 and Y907) and PARP-2 (Y449, F450, A451, S457 and Y460) showed strong interactions with the compounds. To comprehend the unbinding mechanism of MNP-4 complexed with PARP-1/2, steered molecular dynamics (SMD) simulations were performed. We concluded from the free energy landscape (FEL) map that PARP-1/2 are well-stabilised when the compound MNP-4 is bound rather than being pulled away from its binding pockets. This finding provides significant evidence regarding PARPi, which could potentially be employed in the therapeutic treatment of HGSOC.

Computational investigations into structure and function impact of novel mutations identified in targeted exons from ovarian cancer cell lines

The lack of sensitive and specific biomarkers for ovarian cancer leads to late stage diagnosis of the disease in a majority of the cases. Mutation accumulation is the basis for cancer progression, thus identifying mutations is an important step in the disease diagnosis. In the present study, a comprehensive analysis of fifteen Next Generation Sequencing samples from thirteen ovarian cancer cell lines was carried out for the identification of new mutations. The study revealed eight clinically significant novel mutations in six ovarian cancer oncogenes, viz. SMARCA4, ARID1A, PPP2R1A, CTNNB1, DICER1 and PIK3CA. In-depth computational analysis revealed that the mutations affected the structure of the proteins in terms of stability, solvent accessible surface area and molecular dynamics. Moreover, the mutations were present in functionally significant domains of the proteins, thereby adversely affecting the protein functionality. PPI network for SMARCA4, CTNNB1, DICER1, PIK3CA, PPP2R1A and ARID1A showed that these genes were involved in certain significant pathways affecting various hallmarks of cancer. For further validation,

Rhamnetin, a nutraceutical flavonoid arrests cell cycle progression of human ovarian cancer (SKOV3) cells by inhibiting the histone deacetylase 2 protein

Overexpression of HDAC 2 promotes cell proliferation in ovarian cancer. HDAC 2 is involved in chromatin remodeling, transcriptional repression, and the formation of condensed chromatin structures. Targeting HDAC 2 presents a promising therapeutic approach for correcting cancer-associated epigenetic abnormalities. Consequently, HDAC 2 inhibitors have evolved as an attractive class of anti-cancer agents. This work intended to investigate the anti-cancer abilities and underlying molecular mechanisms of Rhamnetin in human epithelial ovarian carcinoma cells (SKOV3), which remain largely unexplored. We employed various

Pharmacological network study on the effect of 6-gingerol on cervical cancer using computerized databases

Cervical cancer (CC) is the most frequent cancer in the female population worldwide. Although there are treatments available, they are ineffective and cause adverse effects. 6-gingerol is an active component in ginger with anticancer activity. This research aims to discover the mechanism by which 6-gingerol act as an anticancer agent on CC through a pharmacological network using bioinformatics databases. From MalaCard, Swiss Target Prediction, Comparative Toxicogenomics Database, and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, we obtained the target genes for 6-gingerol and CC and matched them. We got 26 genes and analyzed them in ShinyGO-0.76.3 and DAVID-Bioinformatics Resources. Then, we generated a protein-protein interaction network in Cytoscape and obtained 12 hub genes. Hub genes were analyzed in Gene Expression Profiling Interactive Analysis and TISIDB. In addition, molecular docking studies were performed between target proteins with 6-gingerol using SwissDock database. Finally, molecular dynamics studies for three proteins with the lowest interaction energy were implemented using Gromacs software. According to gene ontology results, 6-gingerol is involved in processes of apoptosis, cell cycle, and protein kinase complexes, affecting mitochondria and pathways related to HPV infection.

Machine learning and biological evaluation-based identification of a potential MMP-9 inhibitor, effective against ovarian cancer cells SKOV3

MMP-9, also known as gelatinase B, is a zinc-metalloproteinase family protein that plays a key role in the degradation of the extracellular matrix (ECM). The normal function of MMP-9 includes the breakdown of ECM, a process that aids in normal physiological processes such as embryonic development, angiogenesis, etc. Interruptions in these processes due to the over-expression or downregulation of MMP-9 are reported to cause some pathological conditions like neurodegenerative diseases and cancer. In the present study, an integrated approach for ML-based virtual screening of the Maybridge library was carried out and their biological activity was tested in an attempt to identify novel small molecule scaffolds that can inhibit the activity of MMP-9. The top hits were identified and selected for target-based activity against MMP-9 protein using the kit (Biovision K844). Further, MTT assay was performed in various cancer cell lines such as breast (MCF-7, MDA-MB-231), colorectal (HCT119, DL-D-1), cervical (HeLa), lung (A549) and ovarian cancer (SKOV3). Interestingly, one compound viz., RJF02215 exhibited anti-cancer activity selectively in SKOV3. Wound healing assay and colony formation assay performed on SKOV3 cell line in the presence of RJF02215 confirmed that the compound had a significant inhibitory effect on this cell line. Thus, we have identified a novel molecule that can inhibit MMP-9 activity

In vitroandin silicogrowth inhibitory, anti-ovarian & anti-lung carcinoma effects of 1,5 diarylpenta-1,4-dien-3-one as synthetically modified curcumin analogue

The synthesized 1,5 diarylpenta-1,4-dien-3-one derivatives (compounds 1-6) as synthetic curcumin analogues were tested for their potential anticancer activity against human ovarian and lung adenocarcinoma cells. The absorption, distribution, metabolism, excretion, and toxicity (ADMET/pharmacokinetic) parameters of all the compounds were predicted by admetSAR software. The pharmacokinetics, pharmacodynamics and bioactivity scores properties based on Lipinski rule and Ghose filter, calculated with the help of Molinspiration and ChemDraw. Molecular docking evaluation of all the compounds was also performed by using AutoDock Vina and iGEMDOCK against three most common human anticancer targets; epidermal growth factor receptor (EGFR), heat shock protein (Hsp 90-α), and vascular endothelial growth factor receptor-2 (VEGFR2). The obtained results were compared with the reference compound 7 and drugs 8-10 (7: GO-035; 8: Quinazolin; 9: Naquotinib and 10: Ribofuranuronamide). Finding indicates, all the compounds were potentially interacting with VEGFR2 through the average -9.1 binding energy (BE) with closer contact <5.0 Å deep in the active site of the ligand-receptor complex. All the compounds showed excellent oral bioavailability, bioactivity score, and none of the compounds are virtually found to be toxic. Compounds 1-6 were also successfully characterized by the physical properties as well as spectroscopic techniques (FT-IR and

In silico and structure-based assessment to classify VUS identified in the α-helical domain of BRCA2

Breast cancer type 2 susceptibility (BRCA2) protein plays a crucial role in DNA double-strand breaks repair mechanism by homologous recombination. Pathogenic mutations in the

GBP5 and ACSS3: two potential biomarkers of high-grade ovarian cancer identified through downstream analysis of microarray data

Among all malignancies of the reproductive organs, ovarian cancer is the sixth leading cause of death for women. Several factors contribute to the uncontrolled expression of certain genes in cancer thus making them act as oncogenes or tumour suppressors. In this study, we have examined four microarray datasets of high-grade ovarian cancer cells to identify differentially expressed genes (DEGs). 362 and 94 common DEGs were identified as up-regulated and down-regulated, respectively from 119 disease and 31 control samples. The DEGs were further analysed for their gene ontologies (GO), pathway, protein-protein interactions and co-expression. Most of the biological processes were associated with cellular processes, biological regulation, metabolic processes, and developmental processes. Further, regulatory networks were constructed by the DEGs which are also co-expressed and the hub genes were identified. The hub genes targeted by a large number of microRNAs (miRNAs) were further analyzed to reveal their role in the overall survival of cancer patients. Finally, GBP5 and ACSS3 were highlighted as potential biomarkers for ovarian cancer research.Communicated by Ramaswamy H. Sarma.

In-silico analysis reveals Quinic acid as a multitargeted inhibitor against Cervical Cancer

The cervix is the lowermost part of the uterus that connects to the vagina, and cervical cancer is a malignant cervix tumour. One of this cancer's most important risk factors is HPV infection. In the approach to finding an effective treatment for this disease, various works have been done around genomics and drug discovery. Finding the major altered genes was one of the most significant studies completed in the field of cervical cancer by TCGA (The Cancer Genome Atlas), and these genes are TGFBR2, MED1, ERBB3, CASP8, and HLA-A. The greatest genomic alterations were found in the PI3K/MAPK and TGF-Beta signalling pathways, suggesting that numerous therapeutic targets may come from these pathways in the future. We, therefore, conducted a combined enrichment analysis of genes gathered from various works of literature for this study. The final six key genes from the list were obtained after enrichment analysis using GO, KEGG, and Reactome methods. The six proteins against the identified genes were then subjected to a docking-based screening against a library of 6,87,843 prepared natural compounds from the ZINC15 database. The most stable compound was subsequently discovered through virtual screening to be the natural substance Quinic acid, which also had the highest binding affinity for all six proteins and a better docking score. To examine their stability, the study was extended to MM/GBSA and MD simulations on the six docked proteins, and comparative docking-based calculations led us to identify the Quinic Acid as a multitargeted compound. The overall deviation of the compound was less than 2 Å for all the complexes considered best for the biological molecules, and the simulation interaction analysis reveals a huge web of interaction during the simulation.Communicated by Ramaswamy H. Sarma.

Synergistic combination of ritonavir and cisplatin as an efficacious therapy in human cervical cancer cells: a computational drug discovery andin vitroinsight

HIV-protease inhibitor Ritonavir (RTV) is a clinical-stage drug. We exhibit here the synergistic effect of RTV coupled with cisplatin as potential combination therapy for treatment of cervical cancer. Knowledge about the interaction of RTV with the high-expression signatures in cancer is limited. Therefore, we utilized computational techniques to understand and assess the drug-binding affinity and drug-target interaction of RTV with these altered protein signatures. Computational studies revealed the potential interaction ability of RTV along with few other HIV protease inhibitors against these altered cancer targets. All targets exhibited good affinity towards RTV and the highest affinity was exhibited by CYP450 3A4, PDGFR and ALK. RTV established stable interaction with PDGFR and molecular dynamics simulation confirms their frequent interaction for 300 ns. Control docking of PDGFR with standard PDGFR inhibitor exhibited lower binding affinity when compared with RTV-PDGFR complex. In search of drugs as a part of combination therapy to reduce side effects of Cisplatin, this paper further evaluated the effect of combination of RTV and Cisplatin in cervical cancer cells. We propose several combination models that combines anti-viral drug RTV and standard chemotherapeutic agent, Cisplatin to be synergistic with CI value ranging from of 0.01 to 1.14. These observations suggest that anti-viral compound (RTV) could act synergistically with Cisplatin for cervical cancer therapy. However, further studies are warranted to investigate the combinatorial mode of action of RTV and Cisplatin on different molecular pathways to have a translational outcome in cervical cancer.Communicated by Ramaswamy H. Sarma.

Identification of approved drugs with ALDH1A1 inhibitory potential aimed at enhancing chemotherapy sensitivity in cancer cells: an in-silico drug repurposing approach

CircRNA-miRNA-mRNA interactome analysis in endometrial cancer

In recent years, exploring the potential of miRNAs as novel diagnostic, prognostic and diagnostic markers have gained much attention. In current study, we conducted an in-depth circRNA-miRNA-mRNA interactome to reveal significant molecular processes and biological pathways putatively associated with endometrial cancer (EC). Firstly, we retrieved two circRNAs from circad, hsa_circ_0002577 & hsa_circ_0109046, based on their association with the EC. Subsequently, we predicted miRNAs sponging sites in the two circRNAs and the potential target mRNAs of the predicted miRNAs. Sequestered miRNAs target a number of oncogenes (CBL, MET, KRAS), tumor suppressor (CFT R), receptor protein kinases & GT Pase (MET, KRAS, RAB1B), methyltransferases (SET D8), receptors associated factors (T RAF2, GRB2), growth factors (FGF20), autophagy (BECN1, AT G14), apoptotic regulators (BCL2), transcription factors (T Fs) (CREB1, RUNX1, RUNX2) and gene regulators (CCND1, HIF1A); and others, including some novel gene candidates (CREB1, FGF20, IFI27), that have never been implicated in EC earlier. The expression of hsa-miR-433-3p showed significant predictive relevance (Fold Change = 1.8, AUC = 0.736, Mann-Whitney test p-value = 6.1 e- 14) suggesting its predictive relevance in assessing patients' response to chemotherapy. The hsamiR- 188-3p targets autophagic and apoptotic regulators and its upregulation in endometriosis may be used as for the early stage diagnostic purpose. The hsa-miR-502-5p targets SET D8, T RAF2 and others and suggests additional genomic/epigenomic molecular targets for promising therapeutic interventions in EC. Predicted miRNAs target a number of mRNAs having varied functional impacts and offer an in-depth mechanistic insights for expatiating the biological and regulatory role in EC.Communicated by Ramaswamy H. Sarma.

Potential bioactive compound and hub gene identification of endometrial carcinoma using systems biology

Endometrial carcinoma is a frequent cancer of the female genital tract. Endometrial carcinoma accounts for 97% of all uterine malignancies and 3 % of sarcomas that develop from the endometrium's glands. Endometrial cancer is frequently found in its early stages since most women quickly report postmenopausal vaginal hemorrhage. The need for more advanced medications to improve survival in such situations is still unfulfilled. As a result, there is growing interest in employing an herbal treatment to treat endometriosis, which seems to be an effective strategy. We have discovered a few unintended targets (ligands) in our investigation that are active components of common therapeutic herbs. The differentially expressed genes (DEG - target protein) for endometrial cancer were found using the NCBI and CIViC databases. In our investigation, the protein used for docking and simulation was PDB ID: 3THW. Using the Cytoscape server, the gene-encoding protein network has been identified. It was discovered that the Protein 3THW's binding energy to the bioactive substance (Asarone) was -7.15 Kcal/mol. It was discovered that the crucial interacting amino acid residues were ILE648, PHE650, ILE651, VAL802, TYR815, VAL817. The properties of the pharmaceutical target are further investigated by employing a molecular simulation study for 100 ns with NAMD software. Low RMSD and SASA (Solvent accessible surface area), high RMSF, High hydrogen bonds, between Asarone and MSH2 demonstrated their potency as endometrial cancer inhibitor compounds. Based on these analyses we infer that the bioactive substances originating from medicinal plants may be an effective treatment for endometrial cancer.

Mitoxantrone 2HCl’s adroit activity against cervical cancer replication and maintenance proteins: a multitargeted approach

Cervical cancer poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide and resulting in approximately 300,000 deaths yearly, predominantly caused by high-risk human papillomavirus strains (HPV), mainly types 16 and 18. The scenario poses the urgent need of the hour to develop effective treatment strategies that can address the complexity of cervical cancer and multitargeted inhibitor designing that holds promise as it can simultaneously target multiple proteins and pathways involved in its progression and have the potential to enhance treatment efficacy, reduce the likelihood of drug resistance. In this study, we have performed multitargeted molecular docking of FDA-approved drugs against cervical cancer replication and maintenance proteins- Xenopus kinesin-like protein-2 (3KND), cell division cycle protein-20 (4N14), MCM2-histone complex (4UUZ) and MCM6 Minichromosome maintenance (2KLQ) with HTVS, SP and XP algorithms and have obtained the docking and MM\GBSA score ranging from -8.492 to -5.189 Kcal/mol and -58.16 to -39.07 Kcal/mol. Further, the molecular interaction fingerprints identified ALA, THR, SER, ASN, LEU, and ILE were among the most interacted residues, leaning towards hydrophobic and polar amino acids. The pharmacokinetics and DFT of the compound have shown promising results. The complexes were simulated for 100 ns to study the stability by computing the deviation, fluctuations, and intermolecular interactions formed during the simulation. This study produced promising results, satisfying the criteria that Mitoxantrone 2HCl can be a multitargeted inhibitor against cervical cancer proteins-however, experimental validation is a must before human use.

Synthesis and spectroscopic characterizations of hexakis[(1-(4′-oxyphenyl)-3-(substituted-phenyl)prop-2-en-1-one)]cyclotriphosphazenes: theirin vitrocytotoxic activity, theoretical analysis and molecular docking studies

The hexachlorocyclotriphosphaze compound

Synthesis and characterization of copper–based anticancer compound; in vitro interaction studies with DNA/HSA, SOD mimetic, cytotoxic activity and molecular docking investigation

A new copper(II) complex derived from the ligand ethylene [O,O'-bis{5-{(1E)-(2 hydroxyphenyl)methylene]amino} - 2-hydroxybenzoic acid] was designed, synthesized and characterized by spectroscopic (IR, UV-Vis, ESI-MS, X-ray diffraction, EPR and elemental analytical methods

Synthesis, structural characterizations and in vitro cytotoxic activities of new sulfonamide-based Schiff base derivatives

Synthesis of five different new compounds (1-5) were carried out. Their structures were characterized by spectroscopic methods such as Fourier transform infrared, Proton nuclear magnetic resonance, Carbon-13 nuclear magnetic resonance and Elemental analysis. Cytotoxic activities of five new sulfonamide based-Schiff base compounds were determined by MTT assay using A-2780 (human ovarian cancer) and MCF-7 (breast cancer) cell lines. LogIC

Quantitative structure–activity relationships of xanthen-3-one and xanthen-1,8-dione derivatives and design of new compounds with enhanced antiproliferative activity on HeLa cervical cancer cells

Xanthene derivatives have become a group of molecules of great importance in discovering of new anticancer drugs. Recent studies of our group performed on xanthen-3-one and xanthen-1,8-dione derivatives have shown their antiproliferative activity on HeLa cervical cell lines. Obtained IC

4-Bromo-4’-chloro pyrazoline analog of curcumin augmented anticancer activity against human cervical cancer, HeLa cells: in silico-guided analysis, synthesis, and in vitro cytotoxicity

Inspired by the synergistic effects of hetero-aromatic scaffolds on curcumin, a novel array of pyrazoline substituted curcumin analogs was designed. Multi-scale computational studies were carried out to target the proposed analogs on human kinase β (IKK-β), a potential anti-cancer target. In molecular docking analysis, all the eleven molecules were observed to bind the target site and 4-bromo-4'-chloro analog displayed three hydrogen bond interactions with a docking score of -11.534 kcal/mol higher than parent molecule, curcumin (docking score = -7.12 kcal/mol) as the propellant shaped of analogs aided in proper binding with Kinase Domain binding pocket. The molecular dynamics and simulations studies revealed that the stable complexes of lead molecule were developed as the minimal deviations per residue of protein found within the range of 0.11 to 0.92 Å. The proposed compounds were synthesized, characterized and biologically evaluated against human cervical cancer cell line, HeLa, using standard MTT cell assay. Bio-evaluation studies exhibited superior cytotoxic profile for many analogs as Chloro bromo analog with IC

Chloro and bromo-pyrazole curcumin Knoevenagel condensates augmented anticancer activity against human cervical cancer cells: design, synthesis, in silico docking and in vitro cytotoxicity analysis

With an endeavor to develop novel curcumin analogs as potential anti-cancer agents, we designed and synthesized a series of Knoevenagel condensates by clubbing pyrazole carbaldehydes at the active methylene carbon atom of the curcumin backbone. Molecular docking studies were carried out to target the proposed derivatives on human kinase β (IKKβ), a potential anti-cancer target. The chloro derivative displayed five hydrogen bond interactions with a docking score of -11.874 kcal/mol higher than curcumin (docking score = -7.434 kcal/mol). This was supported by the fact that the propellant shaped derivatives fitted aptly into the binding pocket. Molecular simulations studies were also conducted on the lead molecule and the results figured out that the stable complexes were developed as the minimal deviations per residue of protein within the range of 0.11-0.92 Å. The screened compounds were synthesized, characterized and evaluated

Design of a novel multi-epitope vaccine candidate against endometrial cancer using immunoinformatics and bioinformatics approaches

Endometrial cancer (EC) is one of the most common cancers of the female reproductive system. Multi-epitope vaccine may be a promising and effective strategy against EC. In this study, we designed a novel multi-epitope vaccine based on the antigenic proteins PRAME and TMPRSS4 using immunoinformatics and bioinformatics approaches. After a rigorous selection process, 14 cytotoxic T lymphocyte (CTL) epitopes, 6 helper T lymphocyte (HTL) epitopes, and 8 B cell epitopes (BCEs) were finally selected for vaccine construction. To enhance the immunogenicity of the vaccine candidate, the pan HLA DR-binding epitope was included in the vaccine design as an adjuvant. The final vaccine construct had 455 amino acids and a molecular weight of 49.8 kDa, and was predicted to cover 95.03% of the total world population. Docking analysis showed that there were 10 hydrogen bonds and 19 hydrogen bonds in the vaccine-HLA-A*02:01 and vaccine-HLA-DRB1*01:01 complexes, respectively, indicating that the vaccine has a good affinity to MHC molecules. This was further supported by molecular dynamics (MD) simulation. Immune simulation showed that the designed vaccine was able to induce higher levels of immune cell activity, with the secretion of numerous cytokines. The codon adaptation index (CAI) value and GC content of the optimised codon sequences of the vaccine were 0.986 and 54.43%, respectively, indicating that the vaccine has the potential to be highly expressed. The in silico analysis suggested that the designed vaccine may provide a novel therapeutic option for the individualised treatment of EC patients in the future.Communicated by Ramaswamy H. Sarma.