Possible inhibitory effects of hoslundal, hoslundin and hoslunddiol on human lactate dehydrogenases: a bioinformatics proof

Abstract

The development of anti-malarial drugs is of great importance due to the detrimental effects of this disease all around the world. In recent years, bioinformatics tools provide considerable contributions to develop new small molecules which have important bioactivities against many bio-targets. However, biases in the methodologies or aims of the studies in which in silico tools are used may reveal problematic cases. Hoslundal, hoslundin, and hoslunddiol were proposed by Shadrack et al. (2016) to inhibit Plasmodium falciparum lactate dehydrogenase (Pf-LDH) to fight malaria. But these molecules may have potential to inhibit mammalian LDHs. To investigate whether these molecules have inhibitions on mammalian LDHs or not, we studied a comprehensive and comparative molecular docking studies as described in the present paper. According to the results, the vina scores of hoslundal without NADH for Pf-LDH, HM-LDH, HH-LDH were found as -7.5, -7.6 and -8.2 kJ/mol, respectively. Moreover, multiple sequence alignment analysis reveals high similarities among sequences. In the light of molecular studies, hoslundal were found to be connected to Pf-LDH, HM-LDH, HH-LDH (31, 26, 34), (2, -7, 154), (11, 41, 54), respectively. In conclusion, novel small molecules which are developed via in silico tools could show excellent activities against bio-targets of the pathogenic microorganisms. However, it should not be forgotten that active site of the enzymes is conserved, therefore, after a possible proposal of small molecule, its molecular docking and also Swiss-ADME studies should be necessarily carried out.

Keywords

• anti-malarial drugs
• docking
• human lactate dehydrogenase
• Plasmodium falciparum
• malaria

References

1. Berg JM, Tymoczko JL, Stryer L. 2007. Biochemistry, 6th ed. W. H. Freeman and Company, New York.
2. Bragina, ME, Daina, A, Perez MAS, Michielin O, Zoete V. 2022. SwissSimilarity 2021 Web Tool: Novel Chemical Libraries and Additional Methods for an Enhanced Ligand-Based Virtual Screening Experience., Int J Mol Sci. 23(2): 811.
3. Daina A, Michielin O, Zoete, V. 2017. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 7(1):42717.
4. Daina A, Zoete V. 2016. A boiled‐egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem. 11(11): 1117-1121.
5. Gasteiger E, Hoogland C, Gattiker A, Wilkins MR, Appel RD, Bairoch A. 2005. Protein identification and analysis tools on the ExPASy server. The Proteomics Protoc Handb. 571–607.
6. Granchi C, Bertini S, Macchia M, Minutolo F. 2010. Inhibitors of Lactate Dehydrogenase Isoforms and their Therapeutic Potentials, Curr Med Chem. 17(7): 672 – 697.
7. Iacovino LG, Rossi M, Di Stefano G, Rossi V, Binda C, Brigotti M, Tomaselli F, Pasti AP, Dal Piaz F, Cerini S, Hochkoeppler, A. 2022. Allosteric transitions of rabbit skeletal muscle lactate dehydrogenase induced by pH-dependent dissociation of the tetrameric enzyme. Biochimie. 199:23-35.
8. Kayamba F, Faya M, Jacob O, Kushwaha B, Deshwar N, Obakachi VA, Nyamori VO, Karpoormath R. 2021. Bioorganic & Medicinal Chemistry Lactate dehydrogenase and malate dehydrogenase: Potential antiparasitic targets for drug development studies. Bioorg Med Chem. 50:116458.

9. Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, Li, Q, Shoemaker BA, Thiessen PA, Yu B, Zaslavsky L, Zhang J, Bolton EE. 2021. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res. 49:D1388-D1395.
10. Land H, Humble MS. 2018. Yasara: a tool to obtain structural guidance in biocatalytic investigations. Protein Engineering: Methods and Protocols. 43-67.
11. Liu Y, Grimm M, Dai, W. tao, Hou M. chun, Xiao ZX, Cao Y. 2020. CB-Dock: a web server for cavity detection-guided protein–ligand blind docking. Acta Pharmacol Sin. 41:138–144.
12. Penna-Coutinho J, Cortopassi WA, Oliveira AA, França TCC, Krettli AU. 2011. Antimalarial Activity of Potential Inhibitors of Plasmodium falciparum Lactate Dehydrogenase Enzyme Selected by Docking Studies. PLoS ONE. 6(7):e21237.
13. Ren X, Guo X, Liu C, Jing S, Wang T, Wang L, Guan J, Song W, Zhao Y, Shi Y. 2022. Natural flavone hispidulin protects mice from Staphylococcus aureus pneumonia by inhibition of α-hemolysin production via targeting AgrAC Microbiol Res. 261:127071.
14. Shaaban S, Shaker M, Adam S, El-metwaly NM. 2022. Novel organoselenium-based N -mealanilic acid and its zinc (II) chelate: Catalytic, anticancer, antimicrobial, antioxidant, and computational assessments. J Mol Liq. 363:119907.
15. Shadrack DM, Nyandoro SS, Munissi JJE, Mubofu EB. 2016. In Silico Evaluation of Anti-Malarial Agents from Hoslundia opposita as Inhibitors of Plasmodium falciparum Lactate Dehydrogenase (PfLDH) Enzyme. Comput Mol Biosci. 6:23–32.
16. Sievers F, Higgins DG. 2018. Clustal Omega for making accurate alignments of many protein sequences. Protein Sci.27:135–145.
17. Singh R, Vijah B, Purohit R. 2019. Identification of a novel binding mechanism of quinoline based molecules with lactate dehydrogenase of Plasmodium falciparum. Beilstein Arch. 1-16.
18. Vivas L, Easton A, Kendrick H, Cameron A, Lavandera J, Barros D, Gomez F, Heras D, Brady RL, Croft SL. 2005. Plasmodium falciparum: Stage specific effects of a selective inhibitor of lactate dehydrogenase. Exp Parasitol. 111:105-114.
19. Voet D, Voet J. 1995. Biochemistry, 2nd Edition, John Wiley & Sons, Inc., New York, 317
20. UniProt: the universal protein knowledgebase in 2021. Nucleic acids research. 2021. 49.D1: D480-D489.
21. WHO, 2022. Retrieval date 27.11.2022. https://www.who.int/news-room/fact-sheets/detail/malaria.