Pharmacophore modeling, in silico screening, molecular docking and molecular dynamics approaches for potential alpha-delta bungarotoxin-4 inhibitors discovery

Abstract

Background: The alpha-delta bungartoxin-4 (α-δ-Bgt-4) is a potent neurotoxin produced by highly venomous snake species, Bungarus caeruleus, mainly targeting neuronal acetylcholine receptors (nAchRs) and producing adverse biological malfunctions leading to respiratory paralysis and mortality.

Objective: In this study, we predicted the three-dimensional structure of α-δ-Bgt-4 using homology modeling and investigated the conformational changes and the key residues responsible for nAchRs inhibiting activity.

Materials and methods: From the selected plants, which are traditionally used for snake bites, the active compounds are taken and performed molecular interaction studies and also used for modern techniques like pharmacophore modeling and mapping and absorption, distribution, metabolism, elimination and toxicity analysis which may increase the possibility of success.

Results: Moreover, 100's of drug-like compounds were retrieved and analyzed through computational virtual screening and allowed for pharmacokinetic profiling, molecular docking and dynamics simulation.

Conclusion: Finally the top five drug-like compounds having competing level of inhibition toward α-δ-Bgt-4 toxin were suggested based on their interaction with α-δ-Bgt-4 toxin.

Keywords: Acetylcholine receptor; bungarotoxin; molecular docking; molecular dynamics; pharmacophore; venom.

Figure 1

2D structures of selected bioactive phytochemicals used for snake bites. (a) Aristolochic acid I; (b) Edunol; (c) Wedelolactone; (d) Ellagic Acid; (e) 4-nerolidylcatechol; (f) Cabenegrin A-I; (g) Salireposide; (h) Curcumin; (i) Melanins; (j) Cabenegrin A-II

Figure 2

(a) The predicted and simulated structure of α-δ-bgtx-4. (b) Potential energy variation in molecular dynamics simulation. (c) RMSD analysis of simulated structure of α-δ-Bgt-4

Figure 3

(a) The generated pharmacophore model. Molecular overlay of best four Pharmacophore model of (b) CID 6325610. (c) CID 5281813. (d) CID14982. (e) CID44263865

Figure 4

Compounds passed at all levels of ADMET Descriptor analysis

Figure 5

Molecular interaction of α-δ-Bgt-4 with selected inhbitors (a) aristolochic acid-I. (b) Edunol. (c) Wedelolacetone. (d) Ellagic acid. (e) 4-nerolidyleatechol

Figure 6

Molecular interaction of α-δ-Bgt-4with selected inhbitors (a) BTB 06769. (b) BTB00384. (c) BTB02340. (d) BTB04932. (e) BTB05112. (f) BTB13358. (g) BTB13328. (h) BTB00722