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Acetogenins from Annona muricata as potential inhibitors of antiapoptotic proteins: a molecular modeling study.

Antony P, Vijayan R - Drug Des Devel Ther (2016)

Bottom Line: Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers.Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1.These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.

ABSTRACT
Apoptosis is a highly regulated process crucial for maintaining cellular homeostasis and development. The B-cell lymphoma 2 (Bcl-2) family of proteins play a crucial role in regulating apoptosis. Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers. Annona muricata is a tropical plant that belongs to the Annonaceae family and is well known for its anticancer properties. In this study, molecular docking and simulations were performed to investigate the inhibitory potential of phytochemicals present in A. muricata against antiapoptotic proteins of the Bcl-2 family including Bcl-2, B-cell lymphoma extra-large (Bcl-Xl), and Mcl-1. Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1. Binding score and interactions of these acetogenins were notably better than those of currently available synthetic and natural inhibitors. Molecular dynamics simulations of the top-scoring lead molecules established that these molecules could bind strongly and consistently in the active site of Bcl-Xl. These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

No MeSH data available.


Related in: MedlinePlus

Residues of Bcl-Xl that interacted with the bound ligand during the course of the 100 nanoseconds simulation.Notes: (A) Annohexocin, (B) annomuricin A, and (C) muricatocin A.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.
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f4-dddt-10-1399: Residues of Bcl-Xl that interacted with the bound ligand during the course of the 100 nanoseconds simulation.Notes: (A) Annohexocin, (B) annomuricin A, and (C) muricatocin A.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.

Mentions: In order to analyze structural dynamics and stability of annomuricin A, annohexocin and muricatocin A bound to Bcl-Xl, MD simulations were performed for a period of 100 nanoseconds each. During the initial period of the simulations, Bcl-Xl exhibited some degree of fluctuation, indicating that the protein was undergoing structural adaptations. After this initial period, the protein structure stabilized, providing an equilibrated system. Most of the fluctuations were observed in the loops and turns, whereas the other secondary structures remained intact throughout the simulations. During the course of the simulation, annomuricin A stayed firmly in the binding pocket of Bcl-Xl by forming hydrogen bonds, hydrophobic interactions, and water bridges with the critical residues Tyr101, Ser106, Leu108, and Arg139. Besides maintaining these crucial interactions, it also formed new interactions in the active site (Figure 4A). Annohexocin also adapted well to the binding pocket of Bcl-Xl by maintaining the important interactions with the residues in the P2 pocket. Throughout the simulation, annohexocin retained the hydrogen-bond interactions with Ser106, Asp107, and Leu108 residues (Figure 4B). These sustained interactions confirmed the strong binding of the molecule in the active site of Bcl-Xl. Muricatocin A also remained in the P2 pocket by intermittently forming and breaking hydrogen bonds with Phe105, Ser106, Asp107, and Leu108 residues (Figure 4C). In all three docked complexes, water molecules assisted in forming numerous water bridges, thereby making the interactions stronger. To study how the water molecules could contribute to the binding energy, frames were extracted every 10 nanoseconds from the MD simulations. These were then rescored using the same protocol as used for molecular docking. In the case of annomuricin A, average rescored GlideScore of all frames analyzed was −18.10±1.57 kcal/mol and the final frame produced a GlideScore of −19.15 kcal/mol. The average GlideScores of annohexocin and muricatocin A were −19.67±1.50 kcal/mol and −18.98±2.07 kcal/mol, respectively. All three lead molecules exhibited significant improvement from the initially docked GlideScore (Table 2). During the course of the simulation, water molecules played a crucial role by forming a number of direct interactions and bridges between the ligand and amino acids in the binding site of the protein (Figure S6). This contributed to the significant improvement in the binding scores and assisted the acetogenins to bind more favorably in the active site of Bcl-Xl. This finding highlights the significance of considering water molecules while evaluating protein–ligand interactions, especially in drug discovery.


Acetogenins from Annona muricata as potential inhibitors of antiapoptotic proteins: a molecular modeling study.

Antony P, Vijayan R - Drug Des Devel Ther (2016)

Residues of Bcl-Xl that interacted with the bound ligand during the course of the 100 nanoseconds simulation.Notes: (A) Annohexocin, (B) annomuricin A, and (C) muricatocin A.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835113&req=5

f4-dddt-10-1399: Residues of Bcl-Xl that interacted with the bound ligand during the course of the 100 nanoseconds simulation.Notes: (A) Annohexocin, (B) annomuricin A, and (C) muricatocin A.Abbreviation: Bcl-Xl, B-cell lymphoma extra-large.
Mentions: In order to analyze structural dynamics and stability of annomuricin A, annohexocin and muricatocin A bound to Bcl-Xl, MD simulations were performed for a period of 100 nanoseconds each. During the initial period of the simulations, Bcl-Xl exhibited some degree of fluctuation, indicating that the protein was undergoing structural adaptations. After this initial period, the protein structure stabilized, providing an equilibrated system. Most of the fluctuations were observed in the loops and turns, whereas the other secondary structures remained intact throughout the simulations. During the course of the simulation, annomuricin A stayed firmly in the binding pocket of Bcl-Xl by forming hydrogen bonds, hydrophobic interactions, and water bridges with the critical residues Tyr101, Ser106, Leu108, and Arg139. Besides maintaining these crucial interactions, it also formed new interactions in the active site (Figure 4A). Annohexocin also adapted well to the binding pocket of Bcl-Xl by maintaining the important interactions with the residues in the P2 pocket. Throughout the simulation, annohexocin retained the hydrogen-bond interactions with Ser106, Asp107, and Leu108 residues (Figure 4B). These sustained interactions confirmed the strong binding of the molecule in the active site of Bcl-Xl. Muricatocin A also remained in the P2 pocket by intermittently forming and breaking hydrogen bonds with Phe105, Ser106, Asp107, and Leu108 residues (Figure 4C). In all three docked complexes, water molecules assisted in forming numerous water bridges, thereby making the interactions stronger. To study how the water molecules could contribute to the binding energy, frames were extracted every 10 nanoseconds from the MD simulations. These were then rescored using the same protocol as used for molecular docking. In the case of annomuricin A, average rescored GlideScore of all frames analyzed was −18.10±1.57 kcal/mol and the final frame produced a GlideScore of −19.15 kcal/mol. The average GlideScores of annohexocin and muricatocin A were −19.67±1.50 kcal/mol and −18.98±2.07 kcal/mol, respectively. All three lead molecules exhibited significant improvement from the initially docked GlideScore (Table 2). During the course of the simulation, water molecules played a crucial role by forming a number of direct interactions and bridges between the ligand and amino acids in the binding site of the protein (Figure S6). This contributed to the significant improvement in the binding scores and assisted the acetogenins to bind more favorably in the active site of Bcl-Xl. This finding highlights the significance of considering water molecules while evaluating protein–ligand interactions, especially in drug discovery.

Bottom Line: Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers.Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1.These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Science, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates.

ABSTRACT
Apoptosis is a highly regulated process crucial for maintaining cellular homeostasis and development. The B-cell lymphoma 2 (Bcl-2) family of proteins play a crucial role in regulating apoptosis. Overexpressed Bcl-2 proteins are associated with the development and progression of several human cancers. Annona muricata is a tropical plant that belongs to the Annonaceae family and is well known for its anticancer properties. In this study, molecular docking and simulations were performed to investigate the inhibitory potential of phytochemicals present in A. muricata against antiapoptotic proteins of the Bcl-2 family including Bcl-2, B-cell lymphoma extra-large (Bcl-Xl), and Mcl-1. Docking results revealed that the acetogenins, such as annomuricin A, annohexocin, muricatocin A, annomuricin-D-one, and muricatetrocin A/B, exhibited strong binding interactions with Bcl-Xl when compared to Bcl-2 and Mcl-1. Binding score and interactions of these acetogenins were notably better than those of currently available synthetic and natural inhibitors. Molecular dynamics simulations of the top-scoring lead molecules established that these molecules could bind strongly and consistently in the active site of Bcl-Xl. These results suggest that acetogenins could be explored as selective natural inhibitors of Bcl-Xl that could assist in promoting the intrinsic pathway of apoptosis.

No MeSH data available.


Related in: MedlinePlus