In-silico designing of hnRNP B1 inhibitors against lung cancer: a computational approach

Abstract

RNA-binding proteins regulate the maturtarion of mRNA including pre-mRNA splicing, mRNA transport from the nucleus to cytoplasm, the translocation and longevity of transcripts within the cytoplasm as well as translation of the message. One key RNA-binding protein identified in several aspects of this process is heterogeneous ribonuclear ribonucleoprotein B1 (hnRNP B1) and it plays a role in several cellular functions. HnRNP B1 is overexpressed in several cancers including lung and squamous cell carcinoma of various organs, in addition, its mRNA can be detected in the serum of patients with early stage lung cancer and can therefore be used as a biomarker for cancer detection. Furthermore, it can be used as a target for treatment. In the present study hnRNP B1 was used as a target receptor for in silico ligand binding studies using a library of 55 small compounds selected from the current knowledge of lung cancer therapeutic drugs available in the market as well as known inhibitors of hnRNP B1. TSAR studies were carried out for selected compounds from BioMed CAChe to determine docking score and then compared with 7 lactate dehydrogenase inhibitor involved in lung cancer whose IC50 value were known. Results from both software analyses indicated that EGCG was a potent candidate ligand of hnRNP B1 and was selected as a parent compound for pharmacophore modifications to improve the binding affinity and activity against hnRNP B1. A library of 158 compounds was generated after modification of EGCG and molecular modeling and docking identified several analogues with increased binding scores. In addition, pharmacophore studies indicated the significant importance of ring D in EGCG and the formation of H-bonds between the modified ligands and amino acid GLU108 of hnRNPB1. Hence the outcomes of study identify a strategy for the identification of new lead molecules bearing drug-like properties. Future studies are required to validate this approach and measure the efficacy of analogues of compounds identified using in silico approaches.

Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer

“…SiRNA knockdown of HnRNP A2/ B1, which regulates pre-mRNA processing, mRNA metabolism, transportation and is implicated in various cancers, including advanced stage human gliomas, induces apoptosis and Ros generation and reduces the viability, adhesion, migration, invasion, chemoresistance of glioma cell lines (U251 and SHG44), identifying HnRNP A2/B1 as a relevant therapeutic target in gliomas [316]. HnRNPB1 expression correlates with lung cancer development and siRNA HnRNPB1 knockdown promotes A549 lung cancer cell apoptosis [317], and several potential inhibitory small HnRNPB1 binding molecules have also recently been identified amongst lung cancer drugs [318]. In contrast to full length HnRNP L splicing factor, the HnRNP L alternative exon 7 splice variant, which contains a stop codon, promotes head and neck squamous cell carcinogenesis and is therefore a potential target, and SRSF3 splice factor is also autoregulated by an alternative exon 4 splice variant in a manner similar to hnRNP L, and is promoted by hnRNP L. HnRNP L is also overexpressed in liver, lung and prostate cancer and siRNA HnRNP L knockdown inhibits prostate cancer cell proliferation and xenograft tumour growth in mice, and hnRNP L overexpression interacts with p53, cyclin p21 and Bcl2, identifying hnRNP L inhibition as a potential therapeutic strategy in prostate cancer (Fig.…”