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. 2023 Jan;41(1):45-54.
doi: 10.1080/07391102.2021.2003862. Epub 2021 Nov 23.

Identification of megacerotonic acid and a quinazoline derivative from Universal Natural Product Database as potential inhibitors of Trypanosoma brucei brucei alternative oxidase: molecular docking, molecular dynamic simulation and MM/PBSA analysis

Rahma Muhammad Adamu  1 , Bashiru Ibrahim  2 , Mohammed Auwal Ibrahim  2   3 , Emmanuel Oluwadare Balogun  2   3
Affiliations

Identification of megacerotonic acid and a quinazoline derivative from Universal Natural Product Database as potential inhibitors of Trypanosoma brucei brucei alternative oxidase: molecular docking, molecular dynamic simulation and MM/PBSA analysis

Rahma Muhammad Adamu et al. J Biomol Struct Dyn. 2023 Jan.

Abstract

African trypanosomiasis is caused by Trypanosoma brucei subspecies and available drugs against it, are unsatisfactory due to poor pharmacokinetic properties. Trypanosomal Alternative Oxidase (TAO) is an attractive target for anti-trypanosome rational drug discovery because it is essential for parasite-specific ATP generation and absent in the mammalian host. In this study, 360 filtered ligands from the Universal Natural Product Database were virtually screened and docked on T. brucei brucei TAO (PDB-ID 3VVA). From the virtual screening, 10 ligands with binding energy from -10.6 to -9.0 kcal/mol were selected as hits and further subjected pharmacokinetic and toxicity analyses where all of them passed Lipinski's rule of five. Also, the compounds were non-mutagenic, non-tumorigenic and could cross the blood brain barrier. The two topmost hits (UNPD29179; megacerotonic acid and UNPD41551; a quinazoline derivative) interacted with `four glutamates (Glu123, Glu162, Glu213 and Glu266) close to di-iron (2 iron elements) at the catalytic site of the enzyme. Subsequently, 100 ns MD simulations of the two topmost hits were performed using GROMACS where high RMSD values of 0.75 nm (TAO-UNPD29179) and 0.52 nm (TAO- UNPD41551), low residues fluctuations and consistent values of radius of gyration were observed. Moreover, Solvent Accessible Surface Area showed a consistent value of 160 nm2 for both complexes while TAO-UNPD29179 had higher number of hydrogen bonds than the TAO-UNPD41551. Similarly, MM/PBSA calculations indicated that UNPD29179 had higher free binding energy with TAO than UNPD41551. The data suggest that megacerotonic acid and a quinazoline derivative could be potential inhibitors of TAO with improved pharmacokinetic properties.Communicated by Ramaswamy H. Sarma.

Keywords: African trypanosomiasis; molecular docking; molecular dynamic simulation; supernatural database; trypanosomal alternative oxidase.

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Conflict of interest statement

Disclosure statement

The authors declare that they have no conflict of interest in the study.

Figures

Figure 1.
Figure 1.
The 3D and 2D views of UNPD29179 (A and B) and UNPD41551 (C and D) in complex with TAO at a binding region of 3VVA chain A.
Figure 2.
Figure 2.
Molecular dynamics trajectory plots including (A) Root Mean Square Deviation (RMSD) (B) Root Mean Square Fluctuation (RMSF) and (C) Radius of gyration (Rg) of TAO in complex with the top 2 hit compounds (TAO-UNPD29179 and TAO-UNPD41551) over 100 ns.
Figure 3.
Figure 3.
Analyses of Solvent Accessible Surface Area (SASA) (A), hydrogen bond trajectory (B) and free energy-contributory residues (C) of TAO in complex with the top 2 hit compounds (TAO-UNPD29179 and TAO-UNPD41551) in a 100 ns simulation.
Figure 4.
Figure 4.
Boiled egg plot, water partition coefficient (WlogP) vs. Topological polar surface area (TPSA) of the top two hit compounds.
See this image and copyright information in PMC

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