Structure-Based In Silico Approaches Reveal IRESSA as a Multitargeted Breast Cancer Regulatory, Signalling, and Receptor Protein Inhibitor.

Breast cancer begins in the breast cells, mainly impacting women. It starts in the cells that line the milk ducts or lobules responsible for producing milk and can spread to nearby tissues and other body parts. In 2020, around 2.3 million women across the globe received a diagnosis, with an estimated 685,000 deaths. Additionally, 7.8 million women were living with breast cancer, making it the fifth leading cause of cancer-related deaths among women. The mutational changes, overexpression of drug efflux pumps, activation of alternative signalling pathways, tumour microenvironment, and cancer stem cells are causing higher levels of drug resistance, and one of the major solutions is to identify multitargeted drugs. In our research, we conducted a comprehensive screening using HTVS, SP, and XP, followed by an MM/GBSA computation of human-approved drugs targeting HER2/neu, BRCA1, PIK3CA, and ESR1. Our analysis pinpointed IRESSA (Gefitinib-DB00317) as a multitargeted inhibitor for these proteins, revealing docking scores ranging from -4.527 to -8.809 Kcal/mol and MM/GBSA scores between -49.09 and -61.74 Kcal/mol. We selected interacting residues as fingerprints, pinpointing 8LEU, 6VAL, 6LYS, 6ASN, 5ILE, and 5GLU as the most prevalent in interactions. Subsequently, we analysed the ADMET properties and compared them with the standard values of QikProp. We extended our study for DFT computations with Jaguar and plotted the electrostatic potential, HOMO and LUMO regions, and electron density, followed by a molecular dynamics simulation for 100 ns in water, showing an utterly stable performance, making it a suitable drug candidate. IRESSA is FDA-approved for lung cancer, which shares some pathways with breast cancers, clearing the hurdles of multitargeted drugs against breast and lung cancer. This has the potential to be groundbreaking; however, more studies are needed to concreate IRESSA's role.

Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.

The accumulation of senescent cells has an important role in the phenotypical changes observed in ageing and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. Given the involvement of HDACs and the PI3K pathway in senescence, we hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53. Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Our results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, our results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved.

Delineating Pixantrone Maleate's adroit activity against cervical cancer proteins through multitargeted docking-based MM\GBSA, QM-DFT and MD simulation.

Cervical cancer poses a substantial worldwide health challenge, especially in low- and middle-income nations, caused by high-risk types of human papillomavirus. It accounted for a significant percentage of cancer-related deaths among women, particularly in areas with limited healthcare resources, necessitating innovative therapeutic approaches, and single-targeted studies have produced significant results, with a considerable chance of developing resistance. Therefore, the multitargeted studies can work as a beacon of hope. This study is focused on performing the multitargeted molecular docking of FDA-approved drugs with the three crucial proteins TBK1, DNA polymerase epsilon, and integrin α-V ß-8 of cervical cancer. The docking studies using multisampling algorithms HTVS, SP, and XP reveal Pixantrone Maleate (DB06193) as a multitargeted inhibitor with docking scores of -8.147, -8.206 and -7.31 Kcal/mol and pose filtration with MM\GBSA computations with scores -40.55, -33.67, and -37.64 Kcal/mol. We also have performed QM-based DFT and pharmacokinetics studies of the compound and compared it with the standard values, which results in the compound being entirely suitable against cervical cancer proteins. The interaction fingerprints have revealed that PHE, VAL, SER and ALA are the residues among most interactions. We also explore the stability of the multitargeted potential of Pixantrone Maleate through 100ns MD simulations and investigate the RMSD, RMSF and intermolecular interactions between all three proteins-ligand complexes. All computational studies favour Pixantrone Maleate as a multitargeted inhibitor of the TBK1, DNA polymerase epsilon, and integrin α-V ß-8 and can be validated experimentally before use.