Suneetha Yeguvapalli

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and poses significant treatment challenges due to fewer available options. Creating highly specific and precise anticancer therapies continues to be a significant challenge for TNBC. Previous studies showed that combining drugs or adding chemotherapy to other therapies has significantly improved patient prognosis and proved to be an effective strategy for treating TNBC compared to using chemotherapeutic drugs alone targeting TNBC pathways. One such combination is a PARP inhibitor (PARPi) with an immune checkpoint inhibitor (ICI). In this study, we explored the transcriptomic profiles of the combination of Olaparib (a PARP inhibitor) and atezolizumab (a monoclonal antibody targeting PD-L1) in cells derived from African American (AA) and White populations. Cell viability analyses showed that treatment with olaparib, atezolizumab, and their combination reduced cell viability compared with the control condition, with the combination treatment showing a significant effect. Our transcriptional profiling revealed that both up- and down-regulated genes exhibited widespread suppression of proliferation and biosynthesis pathways, along with selective activation of immune and stress-related pathways. Our functional enrichment analysis revealed significant changes in DNA damage response, chromatin organization, RNA regulatory processes, immune signaling, and inflammatory responses. In conclusion, our study’s results provide valuable insights into key features of combination therapy, which may help guide the more targeted development of these regimens.

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and poses significant treatment challenges due to fewer available options. Creating highly specific and precise anticancer therapies continues to be a significant challenge for TNBC. Previous studies showed that combining drugs or adding chemotherapy to other therapies has significantly improved patient prognosis and proved to be an effective strategy for treating TNBC compared to using chemotherapeutic drugs alone targeting TNBC pathways. One such combination is a PARP inhibitor (PARPi) with an immune checkpoint inhibitor (ICI). In this study, we explored the transcriptomic profiles of the combination of Olaparib (a PARP inhibitor) and atezolizumab (a monoclonal antibody targeting PD-L1) in cells derived from African American (AA) and White populations. Our results demonstrated that combining Olaparib (Ola) and Atezolizumab (Atz) significantly reduced cell viability in both AA and White cell lines, compared to either agent alone. Our transcriptional profiling results showed that in both up- and down-regulated genes, there was widespread suppression of proliferation and biosynthetic gene networks, and selective activation of immune and stress-related pathways. Our transcriptional profiling revealed that both up- and down-regulated genes exhibited widespread suppression of proliferation and biosynthesis pathways, along with selective activation of immune and stress-related pathways. Our functional enrichment analysis revealed significant changes in DNA damage response, chromatin organization, RNA regulatory processes, immune signaling, and inflammatory responses. In conclusion, our study’s results provide valuable insights into key features of combination therapy, which may help guide the more targeted development of these regimens.

A myriad of therapeutic candidates targeting SARS-CoV-2 have entered clinical trials; however, the ongoing challenges in SARS-CoV-2 drug discovery, such as adverse effects associated with some therapeutic candidates, necessitate continuous efforts to identify novel therapeutic targets and strategies. This study leverages integrated in silico approaches, encompassing ensemble docking, molecular dynamics (MD) simulations, dynamic unbinding (DUck), and ADMET predictions, to identify novel saquinavir-related antiviral inhibitors targeting the catalytic dyad and oxyanion-hole loop of the SARS-CoV-2 main protease (Mpro). From a library of 33 saquinavir-related analogs, ensemble docking identified three high-affinity ligands (ΔG ≤ -9.8 kcal/mol). Subsequent MD simulations revealed stable Mpro-ligand complexes and significant structural perturbations within the catalytic dyad (His41-Cys145, ΔD_dyad >1.0 Å) and the oxyanion-hole (Gly143-Ser144-Cys145, Δθ_oxy >5°). DUck simulations elucidated a stepwise dissociation mechanism, identifying key hotspot residues critical for ligand binding. Compounds CHEMBL3706523 and CHEMBL3706524 emerged as promising candidates, exhibiting robust interactions and slower dissociation rates (W_QB >6 kcal/mol). These ligands stabilized the receptor and induced conformational changes that may hinder substrate binding, suggesting a potential 'block cluster' mechanism for inhibition. Favorable ADMET profiles further support their potential as drug candidates with low mammalian toxicity. This study provides a strong foundation for experimental validation and the subsequent development of effective antiviral therapies against SARS-CoV-2.

An efficient one-pot Kabachnik-Fields reaction has been carried out for the synthesis of novel α-aminophosphonates under microwave irradiation and solvent-free conditions by 2-hydroxy-1-naphthaldehyde, aromatic amines and dialkyl phosphites using Hydroxyapatite nanoparticles (HAp NPs) as catalyst. The present new protocol is environmentally benign as it offers some interesting and promising features like solvent-free, low cost, safety, minimal waste, atom efficiency, easy work-up, short reaction time and possessing excellent functional group tolerance to structurally diverse derivatives. The title compounds were subjected to antimicrobial activity against bacterial and fungal strains by disc diffusion and MIC methods. Advanced computational tools were also employed to conduct molecular docking and toxicogenomic investigations on target compounds. Employing ensemble-docking approaches, the primary contenders were identified for their potential to bind to the active sites of GlcN-6-P synthase, with PDB IDs 2VF5 and 2POC acting as target receptors. ADMET studies revealed promising drug-like characteristics of these compounds.

The purpose of this study was to determine the cytotoxicity of Lactiplantibacillus plantarum strain RD1 (Lpb RD1), which was isolated and identified from the curd by 16 S rRNA sequencing. The probiotic properties of the isolated strain were studied by bile and NaCl tolerance and the ethyl acetate extract of Ea-LpRD1, was used to determine the toxicity against human breast cancer (MCF-7) cell lines and human embryonic kidney (HEK-293) cell lines by MTT assay. DNA fragmentation assay was carried out to study apoptosis induction. Flow cytometry analysis was done to determine the % of a cell population using the FTIC-Annexin V staining method. RT-PCR was used to assess gene expression levels in both cell lines. The IC₅₀ concentration of the Ea-LpRD1 in MCF-7 cells was 0.30 mg/ml and in HEK-293 was 0.47 mg/ml. The expression levels of the BCL-2 gene anti-apoptotic genes in humans were reduced and BAX, caspase-8, caspase-3, and caspase-9 were an increased expression in MCF-7 cell lines.

The purpose of this study was to determine the cytotoxicity of Lactiplantibacillus plantarum strain RD1 (Lpb RD1), which was isolated and identified from the curd by 16 S rRNA sequencing. The probiotic properties of the isolated strain were studied by bile and NaCl tolerance and the ethyl acetate extract of (Lpb RD1), was used to determine the toxicity against human breast cancer (MCF-7) cell lines and human embryonic kidney (HEK-293) cell lines by MTTassay. DNA fragmentation assay was carried out to study apoptosis induction. Flow cytometry analysis was done to determine the % of a cell population using the FTIC-Annexin V staining method. RT-PCR was used to assess gene expression levels in both cell lines. The IC50 concentration of the ethyl acetate extract of (Lpb RD1), in MCF-7 cells was 0.30mg/ml. The expression levels of the BCL-2 gene anti-apoptotic genes in humans were reduced and BAX, Caspase 8, caspase3, and caspase 9 were an increased expression in MCF-7 cell lines.

Breast cancer is a leading cancer type and one of the major health issues faced by women around the world. Some of its major risk factors include body mass index, hormone replacement therapy, family history and germline mutations. Of these risk factors, estrogen levels play a crucial role. Among the estrogen receptors, estrogen receptor alpha (ERα) is known to interact with tumor suppressor protein p53 directly thereby repressing its function. Previously, we have studied the impact of deleterious breast cancer-associated non-synonymous single nucleotide polymorphisms (nsnps) rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 gene on the p53 DNA-binding core domain. In the present study, we aimed to analyze the impact of these mutations on p53–ERα interaction. To this end, we, have modelled the full-length structure of human p53 and validated its quality using PROCHECK and subjected it to energy minimization using NOMAD-Ref web server. Three-dimensional structure of ERα activation function-2 (AF-2) domain was downloaded from the protein data bank. Interactions between the modelled native and mutant (R110P, P278A, P151T) p53 with ERα was studied using ZDOCK. Machine learning predictions on the interactions were performed using Weka software. Results from the protein–protein docking showed that the atoms, residues and solvent accessibility surface area (SASA) at the interface was increased in both p53 and ERα for R110P mutation compared to the native complexes indicating that the mutation R110P has more impact on the p53–ERα interaction compared to the other two mutants. Mutations P151T and P278A, on the other hand, showed a large deviation from the native p53-ERα complex in atoms and residues at the surface. Further, results from artificial neural network analysis showed that these structural features are important for predicting the impact of these three mutations on p53–ERα interaction. Overall, these three mutations showed a large deviation in total SASA in both p53 and ERα. In conclusion, results from our study will be crucial in making the decisions for hormone-based therapies against breast cancer.

Epigallocatechin gallate (EGCG) is a major polyphenols of green tea may have the possibility to inhibit epidermal growth factor receptor (EGFR) activity and lead to reduce non-small cell lung cancer (NSCLC) progression. However, EGCG has some toxic features; moreover, there is a lack of explorations into the molecular interaction mechanisms of EGCG and the EGFR. In this examination, integration of quantitative structure–activity relationship (QSAR) modeling, pharmacophore-based virtual screening, and ensemble docking approaches were used to predict potential novel EGCG analogs as effective EGFR inhibitors. QSAR modeling of logP and logS predictions and toxicity endpoint investigation for a set of 82 compounds were shown good predictive ability and robustness from the applicability domain and confusion matrix elucidations. Virtual screening and docking studies revealed that seven high potential EGCG analogs as strong EGFR binders. Molecular interactions interpretations indicated some insights into the structural features of ligands that efficiently interfere with mutation possible residues (Gly⁷¹⁹ and Thr⁷⁹⁰) of the EGFR. The hydrogen bonds, hydrophobic interactions, atomic π-cation interactions and salt bridges of ligands are contributing additional stability to receptor structure, which can lead to blocking the intracellular protein-tyrosine kinase activity, including EGFR associated pathways activation in NSCLC. Therefore, this can characterize as a block-cluster mechanism between EGCG analogs and EGFR complexes. In silico anti-EGFR and anticancer activity predictions suggested that, ligands could act as promising pharmacological, anticancer, and drug-like templates of EGFR towards moderating the NSCLC progressions. These results and provided pinpoints could be beneficial to recognize probable therapeutic targets for NSCLC therapy.