Towards Antituberculosis Drugs: Molecular Docking of Curcumin and its Analogues to Pantothenate Synthetase
Catrina Theresa M. Yang1 and Junie B. Billones1,2*
1Department of Physical Sciences and Mathematics, College of Arts and Sciences, and 2Institute of Pharmaceutical Sciences, National Institutes of Health,
University of the Philippines Manila, Padre Faura, Ermita, Manila
Pantothenate synthetase (PS), an enzyme that furnishes an essential precursor of coenzyme A, has been considered as potential target for novel antituberculosis agents. Hence, curcumin, a well-recognized multi-targeted natural product, and its analogues, have been docked to the enzyme. Curcumin analogue 3, having a hydroxyl and methoxy substituents in the aromatic moieties, exhibited the best binding interaction with PS. Its binding energy, as well as that of curcumin and two other analogues (16 and 18), suggests that these compounds are potentially more potent than nafronyl oxalate, a known inhibitor of the enzyme. Like the natural active intermediate, pantoyl adenylate, analogue 3 interacts with 3 amino acids in common: Gln72, Val187, and Met195. Moreover, its ketone oxygens were oriented directly towards the positive surface of the enzyme, providing additional polar interactions.
Tuberculosis, commonly abbreviated as TB, is a bacterial disease caused by the infection of Mycobacterium tuberculosis (MTB) (Corbett et al. 2003). As an airborne disease, it is highly infectious. It afflicts millions of people each year and ranks as the world’s second leading cause of death from an infectious disease, after the human immuno-deficiency virus (HIV). According to World Health Organization (WHO), the estimated number of new cases in 2011 was almost 9 million with 1.4 million TB deaths (990 000 among HIV negative people and 430 000 HIV-associated TB deaths) (WHO 2012). In 2011, there were estimated 630 000 cases of multidrug resistant TB (MDR TB) while new cases of extensively drug resistant TB (XDR TB) is estimated at 40,000 in 2009 (Goldman & Laughon 2009). . . . . . . . . . . . .
ANAND P, THOMAS SG, KUNNUMAKKARA AB, SUNDARAMA C, HARIKUMAR KB, SUNG B, TARAKAN ST, MISRA K, PRIYADARSINI IK, RAJASEKHARAN KN, AGGARWAL BB. 2008. Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. Biochemical Pharm 76: 1590-1611.
CHAN ED, ISEMAN MD. 2002. Current medical treatment for tuberculosis. British Medical J 325: 1282-86.
CHATTOPADHYAY I, BISWAS K, BANDYOPADHYAY U, BANERJEE RK. 2004. Turmeric and curcumin: Biological actions. Curr Med 87: 44-53.
CIULLI A, SCOTT DE, ANDO M, REYES F, SALDANHA SA, TUCK KL, CHIRGADZE DY, BLUNDELL TL, ABELL C. 2008. Inhibition of Mycobacterium tuberculosis pantothenate synthetase by analogues of the reaction intermediate. ChemBioChem 9(16): 2606-11.
CORBETT EL, WATT CJ, WALKER N, MAHER D, WILLIAMS BG, RAVIGLIONE M, DYE, C. 2003. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Internal Med 163: 1009-21.
DAVIES, PDO. 1999. Multi-drug resistant tuberculosis. Retrieved from http://priory.com/cmol/TBMultid.htm
DE R, KUNDU P, SWARNAKAR S, RAMAMURTHY T, CHOWDHURY A, NAIR GB. 2009. Antimicrobial Activity of Curcumin against Helicobacter pylori Isolates from India and during Infections in Mice. Antimicrobial agents and Chemotherapy 53(4): 1592-97.
DELANO WL. 2002. The PyMOL Molecular Graphics System, DeLano Scientific, Palo Alto, CA, USA. Available at http://www.pymol.org
FUCHS JR, PANDIT B, BHASIN D, ETTER JP, REGAN N, ABDELHAMID D. 2009. Structure–activity relationship studies of curcumin analogues. Bioorganic & Medicinal Chemistry Letters 19(7): 2065-69.
GOLDMAN RC, LAUGHON BE. 2009. Discovery and validation of new antitubercular compounds as potential drug leads and probes. Tuberculosis 89: 331-333.
HUNG AW, SILVESTRE HL, WEN S, CIULLI A, BLUNDELL TL, ABELL C. 2009. Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. Angewandte Chemie International Edition 48(45): 8452-56.
HyperChem(TM), Hypercube, Inc., 1115 NW 4th Street, Gainesville, Florida 32601, USA. Available at www.hyper.com
JOHNSON R, STREICHER EM, LOUW, GE, WARREN W, VAN HELDEN PD, VICTOR TC. 2006. Drug resistance in Mycobacterium tuberculosis. Current Issues in Molecular Biology 8: 97-112.
MORRIS GM, GOODSELL DS, HALLIDAY RS, HUEY R, HART WE, BELEW RK, OLSON AJ. 1998. Automated Docking Using a Lamarckian Genetic Algorithm and and Empirical Binding Free Energy Function. Journal of Computational Chemistry 19: 1639-62.
NOLAN CM, GODBERG SV, BUSKIN SE. 1999. Hepatoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. Journal of the American Medical Association 281: 1014-18.
ORMEROD LP, HORSFIELD N. 1996. "Frequency and type of reactions to antituberculosis drugs: observations in routine treatment". Tubercle and Lung Disease 77 (1): 37-42.
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. Journal of Computational Chemistry 25(13): 1605-12 (Available at http://www.cgl.ucsf.edu/chimera). Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) (Available at http:// www.rcsb.org/pdb/)
RAI D, SINGH JK, ROY N, PANDA D. 2008. Curcumin inhibits FtsZ assembly: an attractive mechanism for its antibacterial activity. Biochem J 410(1): 147-155.
SHAH NS, WRIGHT A, BAI GH. 2007. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 13(3): 380-387.
SHANG P, XIA Y, LIU F, WANG X, YUAN Y, HU D, TU D, CHEN Y, DENG P, CHENG S, ZHOU L, MA Y, ZHU L, GAO W, WANG H, CHEN D, YANG L, HE P, WU S, TANG S, LV X, SHU Z, ZHANG Y, YANG Z, CHEN Y, LI N, SUN F, LI X, HE Y, GARNER P, ZHAN S. 2011. Incidence, Clinical Features and Impact on Anti-Tuberculosis Treatment of Anti-Tuberculosis Drug Induced Liver Injury (ATLI) in China. PLoS ONE 6(7): e21836.
SOUTHWORTH K, SNEED B, ROSS L, COOLEY S, SOSA MI, MANOUVAKHOVA A, RASMUSSEN L, WHITE EL, ANATHAN A, FLETCHER TM III, GOLDMAN RC, GOULDING C, EISENBERG D. 2007. Identifying pantothenate synthetase inhibitors of Mycobacterium tuberculosis from a high throughput screen. Presented at the 13th Annual Conference of the Society for Biomolecular Sciences (SBS), Montreal, Canada, April 15-19 2007 (http://taacf.org/publications).
TAJBAKHSH S, MOHAMMADI K, DEILAMI I, ZANDI K, FOULADVAND M, RAMEDANI E. 2008. Antibacterial activity of indium curcumin and indium diacetylcurcumin. Afr J Biotechnol 7(21): 3832-35.
TROTT O, OLSON AJ. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading, Journal of Computational Chemistry 31: 455-461.
TUCK KL, SALDANHA SA, BIRCH LM, SMITH AG, ABELL C. 2006. The design and synthesis of inhibitors of pantothenate synthetase. Org Biomol Chem 4: 3598-3610.
VAN RIE A, ENARSON D. 2006. XDR tuberculosis: an indicator of public-health negligence. The Lancet 368(9547): 1554-56.
VARAINE F, HENKENS M, GOUZARD V. (eds). 2010. Tuberculosis. (5th ed.). Retrieved from http:// www.refbooks.msf.org/MSF_Docs/En/Tuberculosis/ Tuberculosis_en.pdf.
VELAPARTHI S, BRUNSTEINER M, UDDIN R, WAN B, FRANZBLAU SG, PETUKHOV PA. 2008. 5-tertButyl-N-pyrazol-4-yl-4,5,6,7-tetrahydrobenzo[d] isoxazole-3-carboxamide derivatives as novel potent inhibitors of Mycobacterium tuberculosis pantothenate synthetase: initiating a quest for new antitubercular drugs. J Med Chem 51(7): 1999-2002.
WALLACE AC, LASKOWSKI RA, THORNTON JM. 1995. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Engineering 8: 127-134.
WANG S, EISENBERG D. 2003. Crystal structures of pantothenate synthetase from M. tuberculosis and its complexes with its substrates and a reaction intermediate. Prot Sci 12: 1097-1108.
WHITE EL, SOUTHWORTH K, ROSS L, COOLEY S, GILL RB, SOSA MI, MANOUVAKHOVA A, RASMUSSEN L, GOULDING C, EISENBERG D, FLETCHER TM. 2007. A novel inhibitor of Mycobacterium tuberculosis pantothenate synthetase. J Biomol Screening 12: 100-105.
[WHO] World Health Organization. 2012. Global Tuberculosis Report 2012. WHO Press, World Health Organization, Geneva, Switzerland (Retrieved from http://www.who.int/tb/publications/global_report)
YANG Y, GAO P, LIU Y, JI X, GAN M, GUAN Y, HAO X, LI Z, XIAO C. 2011. A discovery of novel Mycobacterium tuberculosis pantothenate synthetase inhibitors based on the molecular mechanism of actinomycin D inhibition. Bioorganic Medicinal Chemistry Letters 21(13): 3943-46.
YEE D, VALIQUETTE C, PELLETIER M, PARISIEN I, ROCHER I, MENZIES D. 2003. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. American Journal of Respiratory and Critical Care Medicine 167(11): 1472-77.