Inhibitory potential of a benzoxazole derivative, 4FI against SNRPG∼RING finger domain protein complex as a lead compound in the discovery of anti-cancer drugs: A molecular dynamics simulation approach

Abstract

Core-splicing proteins such as small nuclear ribonucleoprotein polypeptide G (SNRPG) and retinoblastoma-binding protein 6 (RBBP6) have been in the spotlight for years because of their regulatory functions in mRNA processing and active engagement in carcinogenesis and tumour growth. Varied forms of cancer have been shown to exhibit different amounts of expression of the two proteins. RBPP6 has been linked to liver, lung, breast, colon, and cervical carcinomas, while SNRGP expression has been found in malignancies of the breast, lung, prostate, and colon. Suggestive evidence has postulated possible involvement between SNRPG and the RBBP6 through its RING finger domain. However, the precise mechanisms of interaction in different types of cancers remain elusive and yet to be characterized. As a result, the capacity to investigate the two proteins in PPI-focused drug development may yield synthetic small molecule smart-drugs against cancer. Using Raccoon and Autodock tools, we present the computationally determined interaction between SNRPG and the RING finger domain of RBBP6. Based on the docked protein complex, a small molecule inhibitor, (2R)-2-[(2-methyl-5-phenyl-pyrazol-3-yl) carbonylamino]-3-naphthalen-2-yl-propanoic acid (4FI), was identified using I-TASSER structure prediction and then docked onto the SNPRG ∼ RING finger domain complex for molecular dynamics (MD) simulations. Binding free energy calculations revealed that the binding affinity of the inhibitor to the complex is −27.96 kcal/mol, indicating a very strong level of interaction. Increased inhibitory efficacy against the complex implies that the 4FI ligand could be employed as a “lead molecule” in the development of novel PPI-targeted anti-cancer drugs.