MOLECULAR DOCKING STUDY OF 1‑(PYRIDIN-4-YL)PYRROLIDINE-2-ONE DERIVATE AGAINST PROLYL-tRNA SYNTHETASE IN PLASMODIUM FALCIPARUM

Yuniarta Tegar Achsendo; Wawo Jesica Ersty; Kesuma Dini

doi:10.36423/pharmacoscript.v5i2.1003

Authors

Yuniarta Tegar Achsendo Faculty of Pharmacy, University of Surabaya
Wawo Jesica Ersty Faculty of Pharmacy, University of Surabaya
Kesuma Dini Faculty of Pharmacy, University of Surabaya

DOI:

https://doi.org/10.36423/pharmacoscript.v5i2.1003

Keywords:

antimalaria, molecular docking, pyridine-pyrolidine, prolyl-tRNA synthetase, stereochemistry

Abstract

Prolyl-tRNA synthetase is one of the novel targets to develop antimalarial drug candidate. Several class of inhibitors have been identified for the enzyme, one of which is pyridine-pyrrolidinone derivative. It is recently known that 4‐[3‐cyano‐3‐(1‐methylcyclopropyl)‐2‐oxopyrrolidin‐1‐yl]‐N‐{[3‐fluoro‐5‐(1‐methyl‐1H‐pyrazol‐4‐yl)phenyl]methyl}‐6‐methylpyridine‐2‐carboxamide possess potent antimalarial activity, possibly via prolyl-tRNA synthetase inhibition. This compound possesses two enantiomeric form which yielded antimalarial bioactivity in different magnitude. It is argued that this compound occupies ATP binding site. However, 3D structure of ligand-protein complex has yet to be elucidated. This study aimed to predict binding mode and affinity of two enantiomers of 4‐[3‐cyano‐3‐(1‐methylcyclopropyl)‐2‐oxopyrrolidin‐1‐yl]‐N‐{[3‐fluoro‐5‐(1‐methyl‐1H‐pyrazol‐4‐yl)phenyl]methyl}‐6‐methylpyridine‐2‐carboxamide using molecular docking approach with EasyDockVina 2.2. The results showed that S enantiomer possess better ligand affinity (-0.81±3.98) compared to R enantiomer (1.74±2.71). The result was in line with in vitro antimalarial assay, which stated the potency of S enantiomer more than R enantiomer. In addition, it is argued that residue GLN475 and THR478 plays important role in ligand-enzyme interaction. Further studies are needed to verify the result with more robust in silico method and enzymatic bioassay.

References

Adachi, R., Okada, K., Skene, R., Ogawa, K., Miwa, M., Tsuchinaga, K., Ohkubo, S., Henta, T. & Kawamoto, T. (2017). Discovery of a novel prolyl-tRNA synthetase inhibitor and elucidation of its binding mode to the ATP site in complex with L-proline. Biochemical and Biophysical Research Communications; 488(2); 393-99.

Biovia, Dassault Système, Discovery Studio Visualizer 2020, San Diego: Dassault Système, 2021.

Bolcato, G., Cuzzolin, A., Bissaro, M., Moro, S. & Sturlese, M. (2019). Can We Still Trust Docking Results? An Extension of the Applicability of DockBench on PDBbind Database. International Journal of Molecular Sciences; 20(14); 3558.

ElTijani, A., Alsafi, M.Y. & Ahmed, A.F. (2019). EasyDockVina: Graphical Interface for Ligand Optimization and High Throughput Virtual Screening with Vina. Zenodo.

Gasteiger J., Marsili M. (1980). Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron. 36(22): 3219-28.

Hammer, Ø., Harper, D.A.T. & Ryan, P.D. (2001). PAST: PALEONTOLOGICAL STATISTICS SOFTWARE PACKAGE FOR EDUCATION AND DATA ANALYSIS. Palaeontologica Electronica. 4(9).

Herman, J.D., Pepper, L.R., Cortese, J.F., Estiu, G., Galinsky, K., Zuzarte-Luis, V., Derbyshire, E.R., Ribacke, U., Lukens, A.K., Santos, S.A., Patel, V., Clish, C.B., Sullivan Jr., W.J., Zhou, H., Bopp, S.E., Schimmel, P., Lindquist, S., Clardy, J., Mota, M.M., Keller, T.L., Whitman, M., Wiest, O., Wirth, D.F. & Mazitschek, R. (2015). The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs. Science Translational Medicine; 7(288); 288ra77.

Hewitt, S.N., Dranow, D.M., Horst, B.G., Abendroth, J.A., Forte, B., Hallyburton, I., Jansen, C., Baragaña, B., Choi, R., Rivas, K.L., Hulverson, M.A., Dumais, M., Edwards, T.E., Lorimer, D.D., Fairlamb, A.H., Gray, D.W., Read, K.D., Lehane, A.M., Kirk, K., Myler, P.J., Wernimont, A., Walpole, C., Stacy, R., Barrett, L.K., Gilbert, I.H. & Van Voorhis, W.C. (2017). Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA Synthetase. ACS Infectious Diseases; 3(1); 34-44.

Jain, A.N. & Nicholls, A. (2008). Recommendations for evaluation of computational methods. Journal of Computer-Aided Molecular Design; 22(3-4); 133-9.

Jain, V., Kikuchi, H., Oshima, Y., Sharma, A. & Yogavel, M. (2014). Structural and functional analysis of the anti-malarial drug target prolyl-tRNA synthetase. Journal of Structural and Functional Genomics; 15(4); 181-90.

Jain, V., Yogavel, M., Oshima, Y., Kikuchi, H., Touquet, B., Hakimi, M-A. & Sharma, A. (2015). Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis. Structure; 23(5); 819-29.

Jain, V., Yogavel, M., Kikuchi, H., Oshima, Y., Hariguchi, N., Matsumoto, M., Goel, P., Touquet, B., Jumani, R.S., Tacchini-Cottier, F., Harlos, K., Huston, C.D., Hakimi, M-A. & Sharma, A. (2017). Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis. Structure; 25(10); 1495-505.

Kalervo Airas R. (2007). Magnesium dependence of the measured equilibrium constants of aminoacyl-tRNA synthetases. Biophysical Chemistry; 131; 29-35.

Keller, T.L., Zocco, D., Sundrud, M.S., Hendrick, M., Edenius, M., Yum, J., Kim, Y-J., Lee, H-K., Cortese, J.F., Wirth, D.F., Dignam, J.D., Rao, A., Yeo, C-Y., Mazitschek, R. & Whitman, M. (2002). Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nature Chemical Biology; 8; 311-17.

Koshland Jr., D.E. (1995). The Key-Lock Theory and the Induced Fit Theory. Angewandte Chemie International Edition in English; 33(2324); 2375-8.

Kramer, B., Rarey, M. & Lengauer, T. (1999). Evaluation of the FLEXX Incremental Construction Algorithm for Protein–Ligand Docking. Proteins; 37; 228-41.

Mai, H.D.T., Thanh, G.V., Tran, V.H., Vu, V.N., Vu, V.L., Truong, B.N., Phi, T.D., Chau, V.M. & Pham, V.C. (2014). Synthesis of febrifuginol analogues and evaluation of their biological activities. Tetrahedron Letters; 55(52); 7226-8.

Maldonado-Rojas, W. Salinas-Torres, J. & Olivero-Verbel, J. (2021). Identification of Potential Human Protein Targets for Soybean Isoflavones. Journal of Brazilian Chemical Society; 32(4);767-76.

Mayo, S.L., Olafson, B.D. & Goddard, W.A. (1990). DREIDING: a generic force field for molecular simulations. Journal of Physical Chemistry; 94; 8897-909.

Nguyen, N.T., Nguyen, T.H., Pham, T.N.H., Huy, N.T., Bay, M.V., Pham, M.Q., Nam, P.C., Vu, V.V. & Ngo, S.T. (2020). Autodock Vina Adopts More Accurate Binding Poses but Autodock4 Forms Better Binding Affinity. Journal of Chemical Information and Modelling; 60; 204-11.

Okaniwa, M., Shibata, A., Ochida, A., Akao, Y., White, K.L., Shackleford, D.M., Duffy, S., Lucantoni, L., Dey, S., Striepen, J., Yeo, T., Mok, S., Aguiar, A.C.C., Sturm, A., Crespo, B., Sanz, L.M., Churchyard, A., Baum, J., Pereira, D.B., R.V.C., Guido, Dechering, K., J., Wittlin, S., Uhlemann, A-C., Fidock, D.A., Niles, J.C., Avery, V.M., Charman, S.A. & Laleu, B. (2021). Repositioning and Characterization of 1-(Pyridin-4-yl) yrrolidine-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors. ACS Infectious Disease; 7(6); 1680-9.

Penningroth, SM., Olehnik, K. & Cheung, A. (1980). ATP Formation from Adenyl-5”yl Imidodiphosphate, a Nonhydrolyzable ATP Analog. Journal of Biological Chemistry; 255(20); 9545-8.

Pinzi, L. & Rastelli, G. (2019). Molecular Docking: Shifting Paradigms in Drug Discovery. International Journal of Molecular Sciences; 20; 4331.

Prieto-Martínez, F.D., Arciniega, M. & Medina-Franco, J.L. (2018). Molecular docking: current advances and challenges. TIP Revista Especializada en Ciencias Químico-Biólogicas; 21(Supl.1); 65-87.

Singh, U.C. & Kollman, P.A. (1984). An approach to computing electrostatic charges for molecules. Journal of Computational Chemistry; 5(2); 129-45.

Torres, P.H.M., Sodero, A.C.R., Jofily, P. & Silva Jr, F.P. (2019). Key Topics in Molecular Docking for Drug Design. International Journal of Molecular Sciences; 20(18); 4574.

Triggle, D.J. (1997). Stereoselectivity of drug action. Drug Discovery Today; 2(4); 138-47.

Trott, O. & Olson, A.J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry; 31(2); 455-61.

Vargesson, N. (2015). Thalidomide-induced teratogenesis: History and mechanisms. Birth Defects Research Part C: Embryo Today: Reviews; 105(2); 140-56.