TY  - JOUR
T1  - Comprehensive Structure-Based In Silico Identification of IRESSA as a Multitarget Inhibitor of Key Breast Cancer Signaling Proteins
A1  - Thomas Berger
A1  - Nina Keller
A1  - Stefan Huber
JF  - Pharmaceutical Sciences and Drug Design
JO  - Pharm Sci Drug Des
SN  - 3062-4428
Y1  - 2024
VL  - 4
IS  - 1
DO  - 10.51847/WuSdslncsI
SP  - 212
EP  - 229
N2  - Breast cancer originates in breast tissue cells and primarily affects women. It typically begins in the cells lining the milk ducts or the lobules that produce milk, with the potential to invade surrounding tissues and metastasize to distant parts of the body. In 2020, approximately 2.3 million women worldwide were diagnosed with the disease, resulting in an estimated 685,000 deaths. Furthermore, 7.8 million women were alive with a breast cancer diagnosis, establishing it as the fifth leading cause of cancer mortality in women. Elevated drug resistance arises from mutational alterations, overexpression of drug efflux pumps, activation of alternate signalling pathways, the tumour microenvironment, and cancer stem cells; a key strategy to overcome this is the development of multitargeted therapeutics. In the present study, we performed extensive virtual screening employing HTVS, SP, and XP docking protocols, followed by MM/GBSA calculations, on FDA-approved drugs against the targets HER2/neu, BRCA1, PIK3CA, and ESR1. The results identified IRESSA (Gefitinib-DB00317) as a multitargeted inhibitor of these proteins, exhibiting docking scores from −4.527 to −8.809 kcal/mol and MM/GBSA values ranging from −49.09 to −61.74 kcal/mol. Interacting residues were utilised as fingerprints, with 8LEU, 6VAL, 6LYS, 6ASN, 5ILE, and 5GLU emerging as the most frequently involved. ADMET profiles were subsequently evaluated and benchmarked against QikProp standard ranges. The investigation was further extended to DFT calculations using Jaguar, generating electrostatic potential maps, HOMO and LUMO distributions, and electron density plots, followed by 100 ns molecular dynamics simulations in aqueous solvent that demonstrated exceptional stability, supporting its viability as a drug candidate. IRESSA is already FDA-approved for lung cancer, which shares certain pathways with breast cancer, thereby facilitating its potential repurposing as a multitargeted agent for both malignancies. This approach holds considerable promise, although additional investigations are required to substantiate IRESSA’s efficacy in this context.  
UR  - https://galaxypub.co/article/comprehensive-structure-based-in-silico-identification-of-iressa-as-a-multitarget-inhibitor-of-key-b-vgwcvuvbrfettv2
ER  -