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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

Chemical structures of (A) lead acetogenins and (B) inhibitors. Chiral centers are marked with an asterisk (*).
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f1-dddt-10-1399: Chemical structures of (A) lead acetogenins and (B) inhibitors. Chiral centers are marked with an asterisk (*).

Mentions: To explore the possible binding patterns and interactions of phytocompounds to Bcl-2, Bcl-Xl, and Mcl-1, molecular docking and simulation approaches were employed. The 65 ligands used for XP docking were evaluated using GlideScore and binding energies. The results were analyzed based on their interactions in the active site of these antiapoptotic proteins. Table 2 lists the top-ranked molecules in Bcl-Xl and Bcl-2 along with the interacting residues. In Bcl-Xl, five acetogenins, namely, annomuricin A, annohexocin, muricatocin A, muricatetrocin A/B, annomuricin-D-one (Figure 1A), exhibited high GlideScore ranging from −13.00 kcal/mol to −11.21 kcal/mol in one structure (3ZLR) and from −12.59 kcal/mol to −10.60 kcal/mol in the other (4QVX). In Bcl-2 proteins, the acetogenins muricin E, annomuricin A, and annohexocin came on top with Glide-Scores ranging from −9.32 kcal/mol to −8.80 kcal/mol in 2W3L and from −9.89 kcal/mol to −9.58 kcal/mol in 4AQ3.


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

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

Chemical structures of (A) lead acetogenins and (B) inhibitors. Chiral centers are marked with an asterisk (*).
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-10-1399: Chemical structures of (A) lead acetogenins and (B) inhibitors. Chiral centers are marked with an asterisk (*).
Mentions: To explore the possible binding patterns and interactions of phytocompounds to Bcl-2, Bcl-Xl, and Mcl-1, molecular docking and simulation approaches were employed. The 65 ligands used for XP docking were evaluated using GlideScore and binding energies. The results were analyzed based on their interactions in the active site of these antiapoptotic proteins. Table 2 lists the top-ranked molecules in Bcl-Xl and Bcl-2 along with the interacting residues. In Bcl-Xl, five acetogenins, namely, annomuricin A, annohexocin, muricatocin A, muricatetrocin A/B, annomuricin-D-one (Figure 1A), exhibited high GlideScore ranging from −13.00 kcal/mol to −11.21 kcal/mol in one structure (3ZLR) and from −12.59 kcal/mol to −10.60 kcal/mol in the other (4QVX). In Bcl-2 proteins, the acetogenins muricin E, annomuricin A, and annohexocin came on top with Glide-Scores ranging from −9.32 kcal/mol to −8.80 kcal/mol in 2W3L and from −9.89 kcal/mol to −9.58 kcal/mol in 4AQ3.

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