Pharmacoinformatic Approach to Explore the Antidote Potential of Phytochemicals on Bungarotoxin from Indian Krait, Bungarus caeruleus

Abstract

Venomous reptiles especially serpents are well known for their adverse effects after accidental conflicts with humans. Upon biting humans these serpents transmit arrays of detrimental toxins with diverse physiological activities that may either lead to minor symptoms such as dermatitis and allergic response or highly severe symptoms such as blood coagulation, disseminated intravascular coagulation, tissue injury, and hemorrhage. Other complications like respiratory arrest and necrosis may also occur. Bungarotoxins are a group of closely related neurotoxic proteins derived from the venom of kraits (Bungarus caeruleus) one of the six most poisonous snakes in India whose bite causes respiratory paralysis and mortality without showing any local symptoms. In the current study, by employing various pharmacoinformatic approaches, we have explored the antidote properties of 849 bioactive phytochemicals from 82 medicinal plants which have already shown antidote properties against various venomous toxins. These herbal compounds were taken and pharmacoinformatic approaches such as ADMET, docking and molecular dynamics were employed. The three-dimensional modelling approach provides structural insights on the interaction between bungarotoxin and phytochemicals. In silico simulations proved to be an effective analytical tools to investigate the toxin-ligand interaction, correlating with the affinity of binding. By analyzing the results from the present study, we proposed nine bioactive phytochemical compounds which are, 2-dodecanol, 7-hydroxycadalene, indole-3-(4'-oxo)butyric acid, nerolidol-2, trans-nerolidol, eugenol, benzene propanoic acid, 2-methyl-1-undecanol, germacren-4-ol can be used as antidotes for bungarotoxin.

Keywords: Bungarotoxin; Drug design; Molecular docking; Molecular dynamics; Pharmacokinetic profiling; Toxins.

Graphical abstract

Fig. 1

The summarized step-by-step protocol flowchart used in this study: the detailed pipeline procedures from the 3D structure selection to the final inhibitors validation: and the numbers (#) represented the selection of ligand compounds used in each level of analysis.

Fig. 2

Three dimensional structure of alpha-delta-bungarotoxin-4 and its binding site were highlighted with surface view.

Fig. 3

ADMET descriptors of all selected ligand molecules and their Alogp98, absorption and blood brain barrier penetration (BBB) confidence levels (95 and 99) are shown in different color circles.

Fig. 4

Receptor (toxin)–ligand interactions were assessed using molecular docking of α-δ-Bgt-4 with corresponding ligand molecules. Left side of each panel was overall toxin-ligand complex with secondary structure view and right side of the panel was atom level interactions of (A) 2- Dodecanol, (B) 7- Hydroxycadalene, (C) Indole-3-(4'-oxo)butyric acid, (D) Nerolidol-2, (E) Trans-nerolidol, (F) Eugenol, (G) Benzene propanoic acid, (H) 2-methyl-1-undecanol, (I) Germacren-4-ol, (J) overall all interactions of all selected ligands with α-δ-Bgt-4 toxin.

Fig. 4

Receptor (toxin)–ligand interactions were assessed using molecular docking of α-δ-Bgt-4 with corresponding ligand molecules. Left side of each panel was overall toxin-ligand complex with secondary structure view and right side of the panel was atom level interactions of (A) 2- Dodecanol, (B) 7- Hydroxycadalene, (C) Indole-3-(4'-oxo)butyric acid, (D) Nerolidol-2, (E) Trans-nerolidol, (F) Eugenol, (G) Benzene propanoic acid, (H) 2-methyl-1-undecanol, (I) Germacren-4-ol, (J) overall all interactions of all selected ligands with α-δ-Bgt-4 toxin.

Fig. 4

Receptor (toxin)–ligand interactions were assessed using molecular docking of α-δ-Bgt-4 with corresponding ligand molecules. Left side of each panel was overall toxin-ligand complex with secondary structure view and right side of the panel was atom level interactions of (A) 2- Dodecanol, (B) 7- Hydroxycadalene, (C) Indole-3-(4'-oxo)butyric acid, (D) Nerolidol-2, (E) Trans-nerolidol, (F) Eugenol, (G) Benzene propanoic acid, (H) 2-methyl-1-undecanol, (I) Germacren-4-ol, (J) overall all interactions of all selected ligands with α-δ-Bgt-4 toxin.

Fig. 4

Receptor (toxin)–ligand interactions were assessed using molecular docking of α-δ-Bgt-4 with corresponding ligand molecules. Left side of each panel was overall toxin-ligand complex with secondary structure view and right side of the panel was atom level interactions of (A) 2- Dodecanol, (B) 7- Hydroxycadalene, (C) Indole-3-(4'-oxo)butyric acid, (D) Nerolidol-2, (E) Trans-nerolidol, (F) Eugenol, (G) Benzene propanoic acid, (H) 2-methyl-1-undecanol, (I) Germacren-4-ol, (J) overall all interactions of all selected ligands with α-δ-Bgt-4 toxin.

Fig. 5

Graphical representation of the total energy profile of α-δ-Bgt-4 complex with (a)2-dodecanol, (b)7-hydroxycadalene, (c)Indole-3-(4'-oxo) butyric acid, (d)Nerolidol-2, (e)Trans-nerolidol, (f)Eugenol, (g)Benzene propanoic acid, (h)2-methyl-1-undecanol, (i)Germacren-4-ol.

Fig. 6

(a) RMSD value for all top nine toxin-ligand complexes are shown and overall structural level RMSD deviations were recorded for 5000 conformations; (b) Similarly RMSF were calculated for individual amino acid residue level and almost 90% amino acids RMSF were less than 1.6 Å.