Abstract
RAD51 is a core factor for homologous recombination (HR) to repair DNA
double strand breaks and overexpressed in breast cancer cells. Truncated
peptide BRC4 (1523-1537) was obtained by computer simulation which had
the highest binding free energy targeting RAD51. To enhance the binding
affinity to the target protein, six nicotinic acid derivatives were
modified at the N-terminal of BRC4 (1523-1537) by Fmoc solid-state
synthesis to obtain nicotinamide-modified peptides. The interaction of
RAD51 (181-200) with BRC4 (1523-1537) and nicotinamide-modified peptides
were verified by circular dichroism (CD) spectroscopy and fluorescence
spectroscopy. In conclusion, modifying small molecule pharmacophores can
improve binding ability. According to spectral results,
2-chloro-5-fluoronicotinic acid modified BRC4 (1523-1537) has the most
significant influence on the secondary structure of RAD51 (181-200);
binding constant is 1.1×10 4 L·mol
-1. Cell experiments showed that BRC4 (1523-1537)
modified with nicotinic acid N-oxide had the best inhibitory effect on
the proliferation of MDA-MB-231 cells.