Structure-Based Drug Design in Discovering Target Specific Drugs against Plasmodium falciparum Adenylosuccinate Lyase
doi.org/10.26538/tjnpr/v5i4.23
Keywords:
Malaria, Drug design, Antimalarial activity, Molecular docking, Drug target, ADMET propertiesAbstract
The emergence of bioinformatics tools and methods has impressively increased the chances of the discovery of new antimalarial drugs that can act through new modes of action, with high efficacy against the deadly Plasmodium falciparum. An essential protein in the salvage of Plasmodium falciparum purines is adenylosuccinate lyase (ADSL), necessary for the synthesis of parasite’s DNA, and therefore can be a potential antimalarial drug target. Hence, structure-based drug design (SBDD) was employed to screen a large dataset of compounds downloaded from the PubChem database against homology modelled Plasmodium falciparum adenylosuccinate lyase (PfADSL). A total of 1,082 compounds were successfully prepared using PyRX software. This was after 3,697 compounds obtained from the similarity evaluation search on 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) were filtered with Lipinski's rule of five (RO5). AutoDock vina software was employed to perform the virtual screening against the biological target using the downloaded ligands from PubChem database with a center grid of x, y, z set on 15.930, 54.398, -5.213 and grid size of x, y, z set on 80,80, 80. A post-screening analysis showed that the five best hits from the screening possessed better binding affinities, within the ranges of -10.9 and -10.5 (kcal/mol), when compared to AICAR (- 8.6 kcal/mol) and chloroquine (-6.0 kcal/mol) standards. The best hits also showed moderate toxicity and good pharmacokinetic properties. Thus, these compounds could be further validated, optimized, synthesized, and transformed into successful commercially-available antimalarial drugs.
References
Taylor D. The pharmaceutical industry and the future of drug development. RSC Publishing; 2015; 1-33p.
Hughes JP, Rees SS, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol. 2010; 162(6):1239-1249.
Anurak C and Kesara N. A systematic review: Application of in silico models for antimalarial drug discovery. Afr J Pharm Pharmacol. 2018; 12(13):159-167.
Kumar S. Structure-based drug design for Malaria. Chhatrapati Shanu Ji Maharaj University, Kanpur; 2011.
Adane L and Bharatam P V. Computer-aided molecular design of 1H-imidazole-2 , 4-diamine derivatives as potential inhibitors of Plasmodium falciparum DHFR enzyme. J Mol Model. 2010; 17:657-667.
Baba N and Akaho E. VSDK : Virtual screening of small molecules using AutoDock Vina on Windows platform. Bioinf. 2011; 6(10):387-388.
Cheuka PM, Dziwornu G, Okombo J, Chibale K. Plasmepsin Inhibitors in Antimalarial Drug Discovery : Medicinal Chemistry and Target Validation (2000 – Present). J Med Chem. 2020; 63(9):4445-4467.
Rana D, Kalamuddinb M, Sundriyalc S, Jaiswala V, Sharma G, Sarma KD, Sijwali PS, Mohmmed A, Malhotra P, Mahindroo N. Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity. Bioorg Med Chem. 2020; 28(1):115155.
World Health Organization. World malaria report 2019. Geneva, Switzerland; 2019.
Rahila S, Nidhi K, Shahzaib A, D JD, Shakir A, Dinesh G. nsilico profiling and structural insights into the impact of nSNPs in the P. falciparum acetyl-CoA transporter gene to understand the mechanism of drug resistance in malaria. J Biomol Struct Dyn. 2020; 39(2):558-569.
Vangapandu S, Jain M, Kaur K, Patil P, Patel SR, Jain R. Recent advances in antimalarial drug development. Med Res Rev. 2007; 27(1):65-107.
Cassera MB, Zhang Y, Hazleton KZ, Schramm VL. Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum. Curr Top Med Chem. 2012; 11(16):2103-2115.
Bulusu V, Srinivasan B, Bopanna MP, Balaram H. Elucidation of the substrate specificity, kinetic and catalytic mechanism of adenylosuccinate lyase from Plasmodium falciparum. Biochim Biophys Acta - Proteins Proteomics. 2009; 1794(4):642-654.
Kedzierski L, Escalante AA, Isea R, Black CG, Barnwell JW, Coppel RL. Phylogenetic analysis of the genus Plasmodium based on the gene encoding adenylosuccinate lyase. Infect Genet Evol. 2002; 1(2002):297-301.
Marshall VM and Coppel RL. Characterisation of the gene encoding adenylosuccinate lyase of Plasmodium falciparum. Mol Biochem Parasitol. 1997; 88(1-2):237-241.
Ajani OO, Aderohunmu DV, Olorunshola SJ, Ikpo CO, Olanrewaju IO. Facile Synthesis, Characterization and Antimicrobial Activity of 2-Alkanamino Benzimidazole Derivatives. Orient J Chem [Internet]. 2016; 32(1):109-120.
Phillips MA, Stewart MA, Woodling DL, Xie Z-R. Has Molecular Docking Ever Brought us a Medicine? In:
IntechOpen; 2018; 143-178 p.
Dallakyan S and Olson AJ. Small Molecule Library Screening by Docking with PyRx. Methods Mol Biol. 2015; 1263(January):1-11.
Rappe AK, Casewit CJ, Colwell KS, Goddard III WA, Skiff WM. UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. J Am Chem Soc. 1992; 114:10024-10035.
O’Boyle NMO, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel : An open chemical toolbox. J Cheminform. 2011; 3(1):33.
Oduselu GO, Ajani OO, Ajamma YU, Brors B, Adebiyi E. Homology Modelling and Molecular Docking Studies of Selected Substituted Benzo[ d ]imidazol-1-yl)methyl)benzimidamide Scaffolds on Plasmodium
falciparum Adenylosuccinate Lyase Receptor. Bioinform Biol Insights. 2019; 13:1-10.
Ravi L and Krishnan K. A Handbook on Protein-Ligand Docking Tool: AutoDock 4. Innovare J Med Sci. 2016; 4(3):28-33.
Lohning AE, Levonis SM, Williams-Noonan B, Schweiker SS. A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists. Curr Top Med Chem. 2017; 17(18):2023-2040.
Laskowski R and Swindells MB. LigPlot+: multiple ligandprotein intraction diagrams for drug discovery. J Chem Inf Model. 2011; 51:2778-2786.
Vlachakis D. Introductory Chapter. In: Molecular DockingOverview, Background, Application and What the Future Holds Molecular Docking; 2018. 3-9 p.
Iheagwam FN, Ogunlana OO, Ogunlana OE, Isewon I, Oyelade J. Potential Anti-Cancer Flavonoids Isolated From Caesalpinia bonduc Young Twigs and Leaves: Molecular Docking and In Silico Studies. Bioinform Biol Insights. 2019; 13:117793221882137.
Schyman P, Liu R, Desai V, Wallqvist A. vNN web server for ADMET predictions. Front Pharmacol. 2017; 8(DEC): 1-14.
Andricopulo A and Montanari C. Structure-Activity Relationships for the Design of Small-Molecule Inhibitors.Mini-Rev Med Chem. 2005; 5(6):585-593.
Singh IV and Mishra S. Research Article Molecular Docking Studies of Benzamide Derivatives for Pf DHODH Inhibitor as Potent Antimalarial Agent Indra Vikram Singh and Sanjay Mishra. Am J Biochem Mol Biol. 2019; 9(1):1-6.
Feher M and Williams CI. Effect of input differences on the results of docking calculations. J Chem Inf Model. 2009; 49(7):1704-1714.
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