Nagmi Bano

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.

FDA-approved Levophed as an alternative multitargeted therapeutic against cervical cancer transferase, cell cycle, and regulatory proteins

Despite the availability of Pap tests and HPV vaccines, Cervical Cancer continues to be a significant factor contributing to women's deaths. It poses severe consequences to women's health. The disease's severity lies in its potential to progress silently in its early stages, mainly detected in its advanced stage, and clinical treatment is challenging due to drug resistance. This study aims to identify multitargeted lead molecules based on the interactome of Cervical Cancer-related crucial genes, which can help develop drug-resistant therapies. We have considered 9 crucial Cervical Cancer genes, namely BUBR1, CCNB1, FEN1, MAD2, MCM10, MCM6, ITGB8, POLE, and TPX2, to perform gene network analysis and Gene Ontology enrichment studies to identify the potential hub genes and their role. Further, we performed multitarget screening using multisampling algorithms HTVS, SP, and XP to screen the protein products of the 9 genes for their binding affinity for the FDA-approved drugs library. The binding affinities of the compounds were evaluated using MM\GBSA that identified multitargeted potential inhibitor as a Levophed for Cervical Cancer, and the docking results showed a range of MM/GBSA scores, varying from -8.35 to -5.38 kcal/mol for docking, and -43.41 to -19.37 kcal/mol for MM/GBSA scoring. The protein residues that interact the most with Levophed are ALA, THR, ILE, ASN, GLY, ASP, LEU, LYS, VAL, GLN, PRO, CYS, GLU, and TYR. The pharmacokinetic properties and WaterMap computations also support the idea that the compound can potentially become a drug candidate. Furthermore, all 9 complexes were simulated for 100ns, resulting in cumulative deviation and fluctuation of <2 Å, with many intermolecular interactions and binding free energy computations supporting the studies. The study shows that Levophed could treat Cervical Cancer without encountering drug resistance- however, experimental studies are needed to confirm the accuracy.