Exploring Novel Inhibitory Compounds Against Phosphatase Gamma 2: A Therapeutic Target for Male Contraceptives

Abstract

Men have limited options for contraception, despite the widely accepted public health benefits of it, placing the contraceptive burden solely on women. The current study focuses on inhibiting the PP1γ2 enzyme, which plays a role in sperm maturation and motility. The study considered three top compounds based on the findings of molecular docking. The three compounds exhibited a good interaction profile with a binding affinity score of D751-0223 (-8.7 kcal/mol), D751-014 (-8.1 kcal/mol), and N117-0087 (-8 kcal/mol) measured in kcal/mol. Molecular dynamics simulation (MDS) were performed on the PP1γ2-ligand complexes along with the Apo form. The results suggested that all the complexes were stable with no major deviations observed compared to Apo. The average RMSDs for PP1γ2-D751-0223, D751-014, and Apo were 1.27 Å, 1.73 Å, 1.39 Å, and 1.69 Å, respectively. The PP1γ2-ligand complexes were observed with unique salt bridge interactions such as Glu133-Arg137, Asp4-Lys107, Asp188-Arg116, and Glu120-Arg90. The principal component analysis (PCA) findings indicated that every complex had a distinctive motion state. Furthermore, the net MM/PBSA scores for D751-0223, D751-0143, and N117-0087 were -80.01 kcal/mol, -72.18 kcal/mol, and -64.26 kcal/mol, respectively, while the MM/GBSA and MM/PBSA values were -82, -73.07,-67.26 and -80.01, -72.18, -64.26, measured in kcal/mol, respectively. The WaterSwap energy estimation was performed to validate the former technique, and the findings demonstrated that PP1γ2-D751-0223 is a stable complex, with a value of -51.05 kcal/mol. This work provides a baseline to researchers for the identification of novel therapeutic approaches for non-hormonal male contraceptives.

Keywords: MMPBSA/GBSA; binding affinity; contraception; molecular docking; water swap.

Figure 1

The overall systematic computational study initiated with the retrieval of protein, followed by energy minimization and visualization, molecular docking and molecular dynamic simulation, principal component analysis, salt bridges studies, secondary structure analysis, MM-PBSA/GBSA energy computing, and WaterSwap energy estimation.

Figure 2

The surface of the PP1γ2 active pockets (right side); the surface of the Arg132 (yellow), Lys141 (red), Lys147 (black), and Lys150 (blue) active pockets (left side). The purple color shows the active site surface in close view.

Figure 3

The two-dimensional (2D) and three-dimensional (3D) images of the top three hits: D751-0223 (A), D751-0143 (B), and N117-0087 (C), with a close-up view of the binding poses and interactions (D).

Figure 4

Findings of MDs through AMBER xmgrace module. (A) RMSD, (B) RMSF, (C) RoG, and (D) beta factor for D751-0223 (cyan), D751-0143 (yellow), and N117-0087 (purple) in comparison with Apo (Red).

Figure 5

Compounds’ RMSD over simulation time.

Figure 6

The analysis of SASA for D751-0223 (cyan), D751-0143 (yellow), and N117-0087 (purple) in comparison to Apo (red).

Figure 7

The PCA plots of the first two components, PC1 and PC2, for D751-0223-PP1γ2 (A), D751-0143-PP1γ2 (B), N117-0087-PP1γ2 (C), and Apo form (D). Color gradient represents simulation frames (from blue to yellow to red).

Figure 8

The secondary structure studies of D751-0223 (A), D751-0143 (B), N117-0087 (C), and Apo (D) from.