Could the spanning of NAM-AD subsites by poly (ADP ribose) polymerase inhibitors potentiate their selective inhibitory activity in breast cancer treatment? Insight from biophysical computations

Abstract

ABSTRACT Poly (ADP-ribose) polymerase (PARP) inhibition by pharmacological agents has been a useful cancer treatment in recent times. PARP inhibitors represent a category of anticancer drugs that function by blocking PARP catalytic activity. The design of highly selective and effective PARP inhibitors has significant therapeutic advantages and remains an integral part of several PARP-based drug discovery research. We employed conformational landscape and binding energy analyses to decipher the mechanisms underlying the inhibitory potencies and selectivity of Cpd81 towards PARP enzymes. Relatively, the thermodynamics analysis revealed that pp2-cpd81 (−55.38 kcal/mol) had a higher ΔGbind than pp1-cpd81 (−27.97 kcal/mol), indicating high selective binding activity of Cpd81 towards PARP-2. The binding activity of Cpd81 to PARP-2 was potentiated by the high effects of van der Waal. Moreso, the NAM-AD positioning of Cpd81 facilitated its optimal orientation for multiple high-affinity complementary interactions with key site residues. Resultantly, Cpd81 could span the two subsites of the PARP binding pocket effectively, as seen in the multiple interactions exhibited by the compound. These interactions serve as the basis for the selective inhibitory potential of Cpd81. We believe the findings here would pave the way for developing PARP inhibitors that are selective in breast cancer treatment.