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PARP-1 has become an attractive target in cancer treatment owing to its significant role in breast and ovarian cancers. The design of highly selective and effective poly (ADP ribose) polymerase-1 inhibitors has significant therapeutic advantages and has remained the core of several PARP-1-based drug discovery research. The pharmacophoric relevance of a chlorine substituent in a recent study led to the design of compounds 11c (meta-chlorophenyl) and 11d (para-chlorophenyl). In this study, we resolved the mechanistic effects of the changes in chlorine positional orientation, which underlie the inhibitory potencies and selectivity exhibited disparately by 11c and 11d. Compared to 11d, among other multiple higher-affinity complementary interactions with key site residues, the meta-Cl positioning in 11c facilitated its optimal motion and orientation towards conserved residues Arg878 and Asp766 with consistent pi-cation and pi-anion interactions, respectively, thereby favoring the stability of the ligand towards PARP-1. These could account for the higher inhibitory potency exhibited by 11c relative to 11d against PARP-1. The thermodynamics calculation revealed that 11c had a relatively higher total binding energy (ΔGbind) than 11d. We also observed that 11d displayed high deviations, compared to 11c, indicative of its unstable binding orientation. Furthermore, we reported in this study that the high involvement of electrostatic and van der Waal effects potentiated the binding affinity and strength of 11c (ΔE vdW  = −50.58 and ΔE ele  = −27.20) relative to 11d (ΔE vdW  = −49.46 and ΔE ele  = −19.96) at PARP-1 binding pocket. We believe the findings in this current study would provide valuable insights into the design of selective PARP-1 inhibitors containing chlorine substituent for cancer treatment, including lung cancer. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Unveiling the mechanistic roles of chlorine substituted phthalazinone-based compounds containing chlorophenyl moiety towards the differential inhibition of poly (ADP-ribose) polymerase-1 in the treatment of lung cancer