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

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.

In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs

“…The drugs (accolate, sorafenib, loperamide, and mefloquine) were evaluated on SwissADME [ 32 ] web server based on Lipinski’s rule of five and the results are presented in Table 2 and Table 3 . Lipinski’s rule states that an orally active drug has no more than one violation of the following rules; molecular weight ≤500 g/mol, number of hydrogen atom donors ≤5, number of hydrogen atom acceptors ≤10, and the lipophilicity, Log p ≤ 4.15 [ 33 ]. All the drugs satisfied Lipinski’s rules ( Table 2 ); hence, they have accepted drug absorption and permeation.…”

Screening and Elucidation of Chemical Structures of Novel Mammalian α-Glucosidase Inhibitors Targeting Anti-Diabetes Drug from Herbals Used by E De Ethnic Tribe in Vietnam

“… Protein α-glucosidase and the most binding sites (BSs) ( a ) found on α-glucosidase via using the site finder function of the MOE-2015.10 software. The catalytic site prediction of extracellular domain of α-glucosidase ( b ) found via using the CASTp3.0 server [ 35 ]. …”

Alkaloids in Future Drug Discovery

“…According to Ayurveda, the medicinal plant Holarrhena pubescens (Apocynaceae), able to produce steroidal alkaloids, is one of the most common plants used for the treatment of diarrhea. Gupta et al [6] evaluated the in vitro antibacterial activity of an alkaloid fraction of this plant against enterotoxigenic Escherichia coli, which showed significant antibacterial activity, thus validating its use in traditional medicine. Therefore, aiming at finding ligands that would interfere with the binding of the heat-stable enterotoxin secreted by enterotoxigenic Escherichia coli to the extracellular domain of guanylyl cyclase C, an intestinal receptor for heat-stable enterotoxins responsible for diarrhea, the authors carried out an in silico study with steroidal alkaloids from Holarrhena pubescens.…”