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Bromelain: Unveiling its Potential as a Natural Anti-Inflammatory Agent through Effective Binding to Apoptosis-associated Speck-like Containing CARD (ASC)

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Ivan Vito Ferrari^*

This version is not peer-reviewed

Submitted:

07 January 2024

Posted:

08 January 2024

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Abstract

This theoretical study presents a novel perspective on the potential anti-inflammatory properties of Bromelain, a natural agent extracted from pineapple stems. The investigation explores the binding capabilities of Bromelain to Apoptosis-associated speck-like containing CARD (ASC), a crucial adapter molecule known for its involvement in inflammatory processes and inflammasome formation. For the first time, these findings suggest that Bromelain exhibits a notable affinity for ASC, indicating its promising role as a natural anti-inflammatory agent. This study sheds light on the molecular interactions that may contribute to Bromelain's therapeutic potential in modulating inflammatory responses.

Keywords:

Subject: Biology and Life Sciences - Immunology and Microbiology

1. Introduction

The Apoptosis-associated speck-like containing CARD (ASC), also known as PYCARD, is a crucial adapter molecule in inflammatory processes. Its primary role involves the formation of inflammasomes, multiprotein complexes that activate caspases, leading to inflammation and programmed cell death. ASC comprises PYD and CARD domains, facilitating interactions with similar domains in other proteins for inflammasome assembly[1,2,3]. While inflammasome activation is vital for the immune response against infections and cell damage, excessive activation can contribute to chronic inflammatory, autoimmune, or metabolic diseases. Consequently, understanding and regulating ASC and inflammasome activity are significant areas of research for potential therapeutic interventions in inflammation-related disorders[4,5]. The aim of this concise investigation is to examine the interplay between Apoptosis-associated speck-like containing CARD (ASC) and Bromelain through computational methods.Bromelain, known for its capacity to modulate inflammatory states, is composed of enzymes with proteolytic activity primarily extracted from pineapple stems[6,7,8].

The computational method employed to scrutinize potential binding and interactions between ASC and Bromelain at a molecular level was the HDOCK Server.

Broadly speaking, this is a protein-protein or protein-DNA/RNA docking approach based on a hybrid algorithm, incorporating template-based modeling and ab initio free docking[9,10].

Comprehending these interactions may offer insights into how Bromelain could impact ASC-mediated processes, such as inflammasome assembly and inflammation. Given Bromelain's recognized anti-inflammatory properties, investigating its influence on ASC through computational approaches may enhance our understanding of its therapeutic potential in modulating inflammatory responses.

2. Material and Methods

The HDOCK server was employed to predict the binding complexes between two molecules, specifically proteins represented by PDB Code 6U7D (Bromelain precursor used as the receptor) and PDB Code 2KN6 (Apoptosis-associated speck-like protein containing a CARD in CHAIN A used as the ligand). This prediction was carried out using a hybrid docking strategy.

3. Results and Discussion

The objective of this brief study is to explore the interaction between Apoptosis-associated speck-like containing CARD (ASC) and Bromelain using computational methods. Bromelain, recognized for its ability to regulate inflammatory states, is a group of enzymes with proteolytic activity primarily extracted from pineapple stems[6,7,8].

The computational method employed for the analysis of potential binding and interactions between ASC and Bromelain at a molecular level was the HDOCK Server [9,10]. The primary findings are presented in Figure 1, illustrating the outcomes of the interaction study. Table 1 provides the docking results by the HDOCK Server, demonstrating an excellent docking score and potential affinity between Bromelain and Apoptosis-associated speck-like containing CARD. Additionally, Table 2, Table 3, Table 4 and Table 5 outlines the residues at the interface between the two targets.

4. Conclusions

This theoretical study presents a novel perspective on the potential anti-inflammatory properties of Bromelain, a natural agent extracted from pineapple stems. The investigation delves into Bromelain's binding capabilities with Apoptosis-associated speck-like containing CARD (ASC), a pivotal adapter molecule implicated in inflammatory processes and inflammasome formation. This study unveils molecular interactions that may underpin Bromelain's therapeutic potential in modulating inflammatory responses.

References

Koizumi, M., Watanabe, T., Masumoto, J., Sunago, K., Imamura, Y., Kanemitsu, K., ... & Hiasa, Y. (2021). Apoptosis-associated speck-like protein containing a CARD regulates the growth of pancreatic ductal adenocarcinoma. Scientific Reports, 11(1), 22351. [CrossRef]
Tang, X., Liu, X., Wang, Z., Chen, M., & Zhang, D. (2023). Molecular Characterization, Expression, and Regulatory Signal Pathway Analysis of Inflammasome Component Apoptosis-Associated Speck-like Protein Containing a CARD Domain (ASC) in Large Yellow Croaker (Larimichthys crocea). International Journal of Molecular Sciences, 24(3), 2175. [CrossRef]
de Alba, E. (2009). Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). Journal of Biological Chemistry, 284(47), 32932-32941. [CrossRef]
Petrilli, V., Papin, S., & Tschopp, J. (2005). The inflammasome. Current Biology, 15(15), R581. 15.
Man, S. M., & Kanneganti, T. D. (2015). Regulation of inflammasome activation. Immunological reviews, 265(1), 6-21. 1. [CrossRef]
Seligman, B. (1962). Bromelain: An anti-inflammatory agent. Angiology, 13(11), 508-510. [CrossRef]
Pavan, R., Jain, S., & Kumar, A. (2012). Properties and therapeutic application of bromelain: a review. Biotechnology research international, 2012. [CrossRef]
Rathnavelu, V., Alitheen, N. B., Sohila, S., Kanagesan, S., & Ramesh, R. (2016). Potential role of bromelain in clinical and therapeutic applications. Biomedical reports, 5(3), 283-288. [CrossRef]
Yan, Y., Tao, H., He, J., & Huang, S. Y. (2020). The HDOCK server for integrated protein–protein docking. Nature protocols, 15(5), 1829-1852. [CrossRef]
Yan, Y., Zhang, D., Zhou, P., Li, B., & Huang, S. Y. (2017). HDOCK: a web server for protein–protein and protein–DNA/RNA docking based on a hybrid strategy. Nucleic acids research, 45(W1), W365-W373. [CrossRef]

Figure 1. shows the binding region , highlighting the interaction between Bromelain (as the receptor, represented in blue) and Apoptosis-associated speck-like containing CARD (as the ligand, depicted in red).

Table 1. shows the docking results analysis, by HDOCK Server highlighting the interaction between Bromelain and Apoptosis-associated speck-like containing CARD .

Receptor (PDB ID: 6U7D-PDB Chain A ID:2KN6Chain A)

Docking Score (kcal/mol)

-208.89

Confidence Score

0.7646

Ligand rmsd(Å)

62.17

Table 2. shows Receptor interface residue(s) .

VAL 95A 2.149

ASP 96A 3.921

ALA 99A 2.707

ILE 104A 4.247

TRP 106A 3.988

ARG 107A 4.026

ASP 108A 2.023

TYR 109A 0.923

GLY 110A 2.807

ILE 136A 4.971

TYR 137A 1.729

LYS 138A 2.182

ILE 139A 1.108

LYS 140A 2.984

LYS 141A 4.059

GLY 142A 4.302

LEU 144A 4.118

ILE 174A 4.776

LYS 177A 3.584

ASN 201A 3.677

SER 202A 3.068

ALA 203A 3.243

TYR 204A 3.012

THR 206A 2.833

GLY 207A 3.447

TYR 208A 4.345

TYR 221A 0.946

SER 224A 3.491

LYS 225A 2.326

GLN 226A 3.104

TYR 310A 2.250

PRO 311A 3.689

THR 12A 2.204

LEU 313A 4.328

GLU 314A 2.966

SER 315A 2.853

Table 3. shows Ligand interface residue(s) .

MET 1A 2.149

GLY 2A 4.040

ARG 3A 0.946

ALA 4A 4.062

ARG 33A 2.182

GLU 34A 2.023

TYR 36A 2.728

TYR 60A 4.469

LEU 61A 0.923

GLU 62A 2.681

THR 63A 2.326

TYR 64A 3.020

GLU 67A 1.108

LEU 68A 5.000

ASN 71A 3.297

ARG 74A 4.048

ALA 82A 4.754

GLY 83A 3.277

GLN 86A 2.853

ALA 87A 4.392

THR 89A 3.396

HIS 90A 2.204

GLN 91A 2.966

GLY 92A 2.899

SER 93A 3.447

GLY 94A 2.833

ALA 95A 3.422

ALA 96A 4.451

GLY 99A 3.584

ILE 100A 3.054

GLN 101A 3.012

ALA 102A 3.909

PRO 103A 1.729

Table 5. shows Receptor-ligand interface residue pair(s) .

95A - 1A 2.149

95A - 2A 4.040

96A - 1A 4.397

96A - 2A 4.167

96A - 3A 3.921

99A - 1A 2.707

99A - 62A 3.792

104A - 61A 4.247

106A - 63A 4.365

106A - 64A 4.076

106A - 67A 3.988

107A - 34A 4.026

108A - 34A 2.023

108A - 36A 2.728

109A - 33A 4.188

109A - 34A 4.144

109A - 36A 3.403

109A - 60A 4.469

109A - 61A 0.923

109A - 64A 3.020

110A - 33A 2.807

110A - 34A 4.173

136A - 67A 4.971

137A - 103A 1.729

138A - 33A 2.182

138A - 64A 4.683

139A - 63A 4.681

139A - 67A 1.108

139A - 68A 5.000

139A - 71A 4.808

140A - 67A 3.532

140A - 71A 3.297

140A - 74A 4.048

140A - 86A 2.984

140A - 89A 3.396

140A - 90A 4.614

141A - 71A 4.518

141A - 74A 4.059

141A - 86A 4.584

142A - 33A 4.302

142A - 71A 4.416

144A - 33A 4.118

174A - 100A 4.776

177A - 99A 3.584

177A - 100A 3.687

201A - 103A 3.677

202A - 103A 3.068

203A - 103A 3.243

204A - 100A 3.054

204A - 101A 3.012

204A - 102A 3.909

204A - 103A 3.145

206A - 92A 4.127

206A - 93A 4.399

206A - 94A 2.833

206A - 95A 3.422

206A - 96A 4.451

207A - 93A 3.447

207A - 94A 4.592

207A - 95A 4.741

208A - 93A 4.345

221A - 3A 0.946

221A - 62A 4.666

224A - 63A 3.491

225A - 3A 2.779

225A - 4A 4.062

225A - 62A 2.681

225A - 63A 2.326

225A - 67A 4.109

225A - 89A 3.650

226A - 90A 3.104

310A - 90A 2.250

311A - 90A 3.689

312A - 90A 2.204

312A - 91A 4.804

312A - 92A 2.899

312A - 93A 4.147

313A - 86A 4.328

313A - 90A 4.368

313A - 92A 4.823

314A - 87A 4.392

314A - 90A 4.473

314A - 91A 2.966

314A - 92A 4.093

314A - 95A 4.088

315A - 74A 4.883

315A - 82A 4.754

315A - 83A 3.277

315A - 86A 2.853

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