In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies.

Neha Gupta,Archana Chaturvedi,Muthusamy Karthikeyan,Neeta Bhagat,Saurav Kumar Choudhary

doi:10.3390/molecules26144147

Neha Gupta, Archana Chaturvedi + Show 3 more

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https://doi.org/10.3390/molecules26144147

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Abstract

The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein–protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.

Highlights

Diarrhea is a major public health problem in rural parts of India
By the screening of nine steroidal alkaloid ligand types from H. pubescens for their binding affinity towards extracellular domain of guanylyl cyclase c (ECDGC-C), we identified three ligands
These compounds were in close association with the target protein and possessed good drug-like properties, as shown by the molecular dynamics simulations and in silico ADMET prediction, respectively

Summary

Introduction

Diarrhea is a major public health problem in rural parts of India. The disease is usually transmitted by the contamination of drinking water and foods with fecal matter. It is responsible for the morbidity and infant mortality prevalent in areas with poor sanitation and crowded conditions [1,2,3]. One of the important etiological agents for intestinal infection in humans has been reported to be enterotoxigenic E. coli (ETEC). This micro-organism has been reported to be associated with traveler’s diarrhea [5]

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