Identification of potential inhibitors of shikimate kinase from Mycobacterium tuberculosis using in silico approach
Tóm tắt
Shikimate kinase is an enzyme that plays a crucial role in the biosynthesis of aromatic amino acids. It is integral to the fifth step of the shikimate pathway, transferring a phosphoryl group from ATP to shikimate, yielding ADP and shikimate-3-phosphate within Mycobacterium tuberculosis (Mtb). This enzyme is an attractive target for drug discovery, especially against pathogens like Mtb that rely on this pathway. The research aimed to identify innovative inhibitors for Mtb by exploring various naturally occurring and synthetic compounds using an in silico approach. The 3D structure of SK complexed with ligands (EPE), ADP, and essential cofactors (Mg2+, Cl−, Pt+) was obtained from the Protein Data Bank. From public databases (Zinc Database and PubChem), 11,323 compounds were identified, showing potential binding affinity to SK with strong binding affinities. These compounds were carefully filtered using Lipinski’s rule of five and underwent molecular docking and ADMET analyses. Compounds PubChem15478 (− 11.75 kcal/mol), ZINC02838601 (− 11.52 kcal/mol), and ZINC11790367 (− 9.88 kcal/mol) had the best binding energies. These compounds demonstrated favorable physicochemical properties and ADMET profiles. The selected compounds then underwent extensive MD simulations analysis. Concurrently, MD simulations involving SK in conjunction with EPE, ADP, and Mg2+ were performed to evaluate their stability relative to protein–ligand complexes. Encouragingly, two compounds—ZINC11790367 and PubChem15478—formed robust and unyielding complexes, resembling the behavior of bound ligands and cofactors during 50 ns MD simulations. This evidence suggests that these compounds have potential as effective SK inhibitors for Mtb, pending successful experimental validation.
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Tài liệu tham khảo
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Bourne PE (2000) The protein data bank. Nucl Acids Res 28:235–242. www.rcsb.org
Case DA, Ben-Shalom IY, Brozell SR, Cerutti DS, Cheatham TE III, Cruzeiro VWD, Darden TA, Duke RE, Ghoreishi D, Gilson MK, Gohlke H, Goetz AW, Greene D, Harris R, Homeyer N, Huang Y, Izadi S, Kovalenko A, Kurtzman T, Lee TS, LeGrand S, Li P, Lin C, Liu J, Luchko T, Luo R, Mermelstein DJ, Merz KM, Miao Y, Monard G, Nguyen C, Nguyen H, Omelyan I, Onufriev A, Pan F, Qi R, Roe DR, Roitberg A, Sagui C, Schott-Verdugo S, Shen J, Simmerling CL, Smith J, SalomonFerrer R, Swails J, Walker RC, Wang J, Wei H, Wolf RM, Wu X, Xiao L, York DM, Kollman PA (2018) AMBER 2018. University of California, San Francisco
Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Tang Y (2012) AdmetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties
de Azevedo Jr WF, Canduri F, de Oliveira JS, Basso LA, Palma MS, Pereira JH, Santos DS (2002) Molecular model of shikimate kinase from MTB. Biochem Biophys Res Commun 295:142e8
DeLano WL (2002) The PyMOL user’s manual. San Carlos, DeLano Scientific, p 452
Dhaliwal B, Nichols CE, Ren J, Lockyer M, Charles I, Hawkins AR, Stammers DK (2004) Crystallographic studies of shikimate binding and induced conformational changes in MTB shikimate kinase. FEBS Lett 574(1–3):49–54
Ducati RG, Basso LA, Santos DS (2007) Mycobacterial shikimate pathway enzymes as targets for drug design. Curr Drug Targets 8(3):423–435
Isa MA (2020) Comparative modeling and dynamic simulation of UDP-N-acetylmuramoyl-alanine ligase (MurC) from Mycobacterium tuberculosis through virtual screening and toxicity analysis. Life Sci 262:118466
Johansson MU, Zoete V, Michielin O, Guex N (2012) Defining and searching for structural motifs using DeepView/Swiss-PdbViewer. BMC Bioinform 13(1):173
Krell T, Maclean J, Boam DJ, Cooper A, Resmini M, Brocklehurst K, Coggins JR (2001) Biochemical and X-ray crystallographic studies on shikimate kinase: the important structural role of the P-loop lysine. Protein Sci 10(6):1137–1149
Laskowski RA, Swindells MB (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3):3–26
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19(14):1639–1662
Oliveira JS, Pinto CA, Basso LA, Santos DS (2001) Cloning and overexpression in the soluble form of functional shikimate kinase and 5-enolpyruvylshikimate 3-phosphate synthase enzymes from MTB. Protein Expr Purif 22(3):430–435
Parish T, Stoker NG (2002) The common aromatic amino acid biosynthesis pathway is essential in MTB. Microbiology 148(10):3069–3077
Pereira JH, de Oliveira JS, Canduri F, Dias MV, Palma MS, Basso LA, de Azevedo WF (2004) Structure of shikimate kinase from MTB reveals the binding of shikimic acid. Acta Crystallogr D Biol Crystallogr 60(12):2310–2319
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25(13):1605–1612
Ramachandran S, Kota P, Ding F, Dokholyan NV (2011) Automated minimization of steric clashes in protein structures. Proteins Struct Funct Bioinform 79(1):261–270
Sander T, Freyss J, von Korff M, Rufener C (2015) DataWarrior: an open-source program for chemistry aware data visualization and analysis. J Chem Inf Model 55(2):460–473
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45(12):2615–2623
Wallace AC, Laskowski RA, Thornton JM (1996) Derivation of 3D coordinate templates for searching structural databases: application to Ser-His-Asp catalytic triads in the serine proteinases and lipases. Protein Sci 5(6):1001–1013
World Health Organization (2020) Tuberculosis fact sheet. https://www.who.int/news-room/fact-sheets/detail/tuberculosis