Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di‐Substituted Oxadiazole‐Based Dibenzo‐Azepine‐Dione Derivatives on Poly (ADP‐Ribose) Polymerase‐1

Abstract

Numerous studies have established the involvement of Poly (ADP-ribose) Polymerase-1 (PARP-1) in cancer presenting it as an important therapeutic target over recent years. Although homology among the PARP protein family makes selective targeting difficult, two compounds [d11 (0.939 μM) and d21 (0.047 μM)] with disparate inhibitory potencies against PARP-1 were recently identified. In this study, free energy calculations and molecular simulations were used to decipher underlying mechanisms of differential PARP-1 inhibition exhibited by the two compounds. The thermodynamics calculation revealed that compound d21 had a relatively higher ΔG bind than d11. High involvement of van der Waal and electrostatic effects potentiated the affinity of d21 at PARP-1 active site. More so, incorporated methyl moiety in d11 accounted for steric hindrance which, in turn, prevented complementary interactions of key site residues such as TYR889, MET890, TYR896, TYR907. Conformational studies also revealed that d21 is more stabilized for interactions in the active site compared to d11. We believe that findings from this study would provide an important avenue for the development of selective PARP-1 inhibitors.