Identification of PARP12 Inhibitors By Virtual Screening and Molecular Dynamics Simulations

Abstract

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.

Keywords: MD simulations; MMGBSA; PARP12; ZINC-FDA; virtual screening.

FIGURE 1

Optimized protocol employed in this work.

FIGURE 2

(A) Close-up view of the binding pockets (A* and B* encircled by black dotted lines) of the PARP12 enzyme. H-bond interactions between (B) ZINC03830332 (white stick), (C) ZINC03831186 (yellow stick), and PARP12 receptor (in green and blue color cartoon models). (D,E) 2D plot of the complexes.

FIGURE 3

(A) Mutation induced by PARP12 structures, (B) comparison of the RMSD plot, and (C) dynamic motion of projection in the eigenvector 1 vs. 2 and the plot two generated for the MD complexes showing conformational space of Cα-atoms.

FIGURE 4

Root mean square fluctuations (RMSFs) of mutant systems of PARP12 and (A) ZINC03830332, (B) ZINC03830554, (C) ZINC03831186, and (D) ZINC03831189.

FIGURE 5

(A) Rg and (B) SASA fluctuations per residue variation plot analysis of the mutant system and in the presence of compounds with PARP12 at total simulation time.

FIGURE 6

FEL direction of motion and magnitude analysis of the mutant PARP12 (A) and complexes with ZINC03830332 (B), ZINC03830554 (C), ZINC03831186, and (D) ZINC03831189 (E) throughout MD simulations. The color bar denotes the relative free energy value between 0 and 19.1 kcal mol⁻¹.