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Insights into the Inhibition of Mycolic Acid Synthesis by Cytosporone E Derivatives for Tuberculosis Treatment Via an In Silico Multi-target Approach

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Abstract

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a major global health threat. The treatment of TB is hampered by the emergence of multidrug resistance, so there is an urgent need to discover new anti-tubercular agents. Multi-target anti-tubercular agents targeting key proteins involved in mycolic acid biosynthesis represent an effective approach to combat TB. This study used a multi-target computational approach to probe the inhibitory potential of 18 cytosporone E analogues against vital proteins involved in Mtb mycolic acid synthesis (InhA, KasA, and MmpL3) utilizing the Schrodinger suite. Among these, 17 cytosporone E derivatives displayed docking scores ranging from − 8.677 to − 4.617 kcal/mol, which were better than the reference TLM6 (− 3.477 kcal/mol) in KasA. While 7 compounds (1–7) showed higher binding affinity (− 12.418 to − 10.103 kcal/mol) than the InhA co-crystallized ligand AP-124 (− 9.866 kcal/mol) and significant binding (− 9.647 to − 7.279 kcal/mol) against MmpL3. The reference ligand SQ109 showed the highest docking score (− 12.786 kcal/mol) in MmpL3. The seven shortlisted compounds showed acceptable MM-GBSA free binding energy against the three proteins. Further, compounds 1–4 were studied by molecular dynamics (MD) simulations for 100 n and density functional theory (DFT) calculations. Compounds 1–4 and protein showed an average RMSD below 3 Å, reflecting the stability of the compounds with InhA protein. The compounds’ order of increased reactivity and photo-stability according to the DFT data are as follows 1 > 3 > 2 > 4. Also, compounds 1–4 showed favorable ADMET properties (absorption, distribution, metabolism, excretion, and toxicity). Thus, these compounds may be considered for further experimental testing to confirm their potential anti-tubercular activity.

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Data Availability

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

CADD:

Compute aided drug design

EMA:

European Medical Agency

FDA:

Food and Drug Administration

InhA:

Enoyl-acyl protein reductase

KasA:

Beta-ketoacyl-ACP synthase A

MD:

Molecular dynamics

MDR-TB:

Multidrug resistance tuberculosis

MM-GBSA:

Molecular Mechanics Generalized Born and surface area

MMpL:

Mycobacterial Member Protein Large

Mtb :

Mycobacterium tuberculosis

PPW:

Protein preparation wizard

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

TB:

Tuberculosis

TDM:

Trehalose dimycolate

TMM:

Trehalose monomycolate

XDR-TB:

Extensively drug resistance tuberculosis

XP:

Extra precision

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Acknowledgements

We acknowledge Mme Katia Dekimeche from Schrodinger for the technical support and help.

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  1. Abdulrahim A. Alzain, Alaa A. Makki and Walaa Ibraheem contributed equally to this work and share first authorship.

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  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan

    Abdulrahim A. Alzain, Alaa A. Makki & Walaa Ibraheem

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  1. Abdulrahim A. Alzain
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Alzain, A.A., Makki, A.A. & Ibraheem, W. Insights into the Inhibition of Mycolic Acid Synthesis by Cytosporone E Derivatives for Tuberculosis Treatment Via an In Silico Multi-target Approach. Chemistry Africa 6, 1811–1831 (2023). https://doi.org/10.1007/s42250-023-00605-7

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