In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment.

Jian Li,Jinku Bao,Peiling Cai,Nan Zhou

doi:10.3390/ijms17020258

Abstract

Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (−86.8) and amber score (−51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was −177.28 kJ/mol while that of olaparib was −159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.

Highlights

The concept of synthetic lethality has recently emerged in the field of cancer treatment
(ADP-ribose) polymerases (PARPs) inhibitors are a group of chemical compounds that are being developed for cancer treatment under the concept of synthetic lethality
Inhibition of Poly (ADP-ribose) polymerases (PARPs)-1 leads to the accumulation of single-strand breaks (SSBs) that are converted to double strand-strand breaks (DSBs) during DNA replication

Summary

Introduction

The concept of synthetic lethality has recently emerged in the field of cancer treatment. This concept was borrowed from classical genetics to describe situations in which defects in two different genes or pathways together result in cell death, while a defect in one of the two does not affect viability [1,2]. (ADP-ribose) polymerases (PARPs) inhibitors are a group of chemical compounds that are being developed for cancer treatment under the concept of synthetic lethality. Defects in the DNA damage response proteins, such as NBS1, MRE11, ATR, ATM, FANCD2, FANCA, FANCC, Chk, Chk, and ERCC1, confer selective sensitivity to PARP inhibition [10,11,12,13,14]

Methods

Results

Conclusion