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. 2020 Dec 25;26(1):70.
doi: 10.3390/molecules26010070.

Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling

Smith B Babiaka  1   2 , Conrad V Simoben  3 , Kennedy O Abuga  4 , James A Mbah  1 , Rajshekhar Karpoormath  5 , Dennis Ongarora  4 , Hannington Mugo  4 , Elvis Monya  6 , Fidelis Cho-Ngwa  6 , Wolfgang Sippl  3 , E Joel Loveridge  7 , Fidele Ntie-Kang  1   3   8
Affiliations

Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling

Smith B Babiaka et al. Molecules. .

Abstract

A new iboga-vobasine-type isomeric bisindole alkaloid named voacamine A (1), along with eight known compounds-voacangine (2), voacristine (3), coronaridine (4), tabernanthine (5), iboxygaine (6), voacamine (7), voacorine (8) and conoduramine (9)-were isolated from the stem bark of Voacangaafricana. The structures of the compounds were determined by comprehensive spectroscopic analyses. Compounds 1, 2, 3, 4, 6, 7 and 8 were found to inhibit the motility of both the microfilariae (Mf) and adult male worms of Onchocerca ochengi, in a dose-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 μM drug concentrations. The IC50 values of the isolates are 2.49-5.49 µM for microfilariae and 3.45-17.87 µM for adult males. Homology modeling was used to generate a 3D model of the O. ochengi thioredoxin reductase target and docking simulation, followed by molecular dynamics and binding free energy calculations attempted to offer an explanation of the anti-onchocercal structure-activity relationship (SAR) of the isolated compounds. These alkaloids are new potential leads for the development of antifilarial drugs. The results of this study validate the traditional use of V. africana in the treatment of human onchocerciasis.

Keywords: alkaloids; anti-onchocercal; bisindoles; docking; homology modeling; monoindoles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of compounds 1–9. For the bisindoles (1, 7–9), the vobasinyl and iboga subunits are highlighted in blue and red, respectively.
Figure 2
Figure 2
Key NOE (A) and HMBC (B) correlations in compound 1. The vobasinyl and iboga subunits are highlighted in blue and red, respectively.
Figure 3
Figure 3
Homology model of thioredoxin reductase of O. ochengi.
Figure 4
Figure 4
Root mean square deviation (rmsd) of generated homology sampled during 20ns molecular dynamics (MD) simulation with respect to the initial structure versus simulation time.
Figure 5
Figure 5
Binding interactions between the binding site with amino acid side-chains with the compounds; (A) compound 1 shown in green sticks, (B) compound 2 shown in green sticks; (C) compound 3 shown in green sticks, (D) compound 4 shown in green sticks.
See this image and copyright information in PMC

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