Computational approaches to identify novel inhibitors for the drug‐resistant Mycobacterium tuberculosis DprE1 enzyme

Chaitali Dhande; Devanshi Mistry; Anandakrishnan Karthic; Rajshri Singh; Sagar Hindurao Barage

doi:10.22146/ijbiotech.80145

Computational approaches to identify novel inhibitors for the drug‐resistant Mycobacterium tuberculosis DprE1 enzyme

https://doi.org/10.22146/ijbiotech.80145

Chaitali Dhande⁽¹⁾, Devanshi Mistry⁽²⁾, Anandakrishnan Karthic⁽³⁾, Rajshri Singh⁽⁴⁾, Sagar Hindurao Barage^(5*)

(1) School of Biotechnology and Bioinformatics, D.Y. Patil University, CBD Belapur, Navi Mumbai – 400614, Maharashtra, India
(2) Institute of Chemical Technology (ICT), Mumbai ‐ 400019, Maharashtra, India
(3) Amity Institute of Biotechnology, Amity University, Mumbai ‐ Pune Expressway, Bhatan, Post‐Somathne, Panvel ‐ 410206, Maharashtra, India
(4) Amity Institute of Biotechnology, Amity University, Mumbai ‐ Pune Expressway, Bhatan, Post‐Somathne, Panvel ‐ 410206, Maharashtra, India; Centre for Proteomics and Drug Discovery, Amity University, Mumbai ‐ Pune Expressway, Bhatan, Post‐Somathne, Panvel ‐ 410206, Maharashtra, India
(5) Amity Institute of Biotechnology (AIB), Amity University, Maharashtra Mumbai - Pune Expressway, Bhatan, Post-Somathne, Panvel, Mumbai. Maharashtra - 410206; Centre for Computational Biology and Translational Research, Amity University, Mumbai ‐ Pune Expressway, Bhatan, Post‐Somathne, Panvel ‐ 410206, Maharashtra, India
(*) Corresponding Author

Abstract

Mycobacterium tuberculosis causes tuberculosis (TB), which is a common but life‐debilitating disease. The continued development of resistance to frontline anti‐TB drugs such as isoniazid and rifampicin threatens the efficacy of currently available treatment procedures. This highlights the need to explore diverse approaches essential for drug development against multi‐drug‐resistant strains of tuberculosis. Drug development relies on the findings associated with novel protein targets, which play a crucial role in the disease life cycle. DprE1, an enzyme that plays a critical role in the cell wall synthesis of M. tuberculosis, has been recognized as a promising target for drug development. In the present study, based on previous experimental findings, seven mutant models of DprE1 involved in DprE1 resistance are predicted using homology modeling. Further, potential inhibitors are selected based on their efficacy and IC50 values. Shortlisted inhibitors are docked with the wild‐type and mutant structures of DprE1. The deduced inhibitor molecule (ZINC5) is found to possess high potential as a lead inhibitor for all the models of DprE1. It can be used to circumvent drug resistance in the current treatment regime.

Keywords

DprE1; Drug resistant TB; Mycobacterium; Novel inhibitor; Tuberculosis (TB)

Full Text:

Supplementary Material PDF

References

Barage S, Kulkarni A, Pal JK, Joshi M. 2017. Unravelling the structural interactions between PKR kinase domain and its small molecule inhibitors using computational approaches. J. Mol. Graph. Model. 75:322– 329. doi:10.1016/j.jmgm.2017.06.009.

Barage S, Sonawane K. 2014. Exploring mode of phosphoramidon and Aβ peptide binding to hECE-1 by molecular dynamics and docking studies. Protein Pept. Lett. 21(2):140–152. doi:10.2174/09298665113209990091.

Bhat ZS, Rather MA, Maqbool M, Lah HU, Yousuf SK, Ahmad Z. 2017. Cell wall: A versatile fountain of drug targets in Mycobacterium tuberculosis. Biomed. Pharmacother. 95:1520–1534. doi:10.1016/j.biopha.2017.09.036.

Bhutani I, Loharch S, Gupta P, Madathil R, Parkesh R. 2015. Structure, dynamics, and interaction of Mycobacterium tuberculosis (Mtb) DprE1 and DprE2 examined by molecular modeling, simulation, and electrostatic studies. PLoS One 10(3):e0119771. doi:10.1371/journal.pone.0119771.

Colovos C, Yeates TO. 1993. Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Sci. 2(9):1511–1519. doi:10.1002/pro.5560020916.

Dallakyan S, Olson AJ. 2015. Small-molecule library screening by docking with PyRx. Methods Mol. Biol. 1263:243–250. doi:10.1007/978-1-4939-2269-7_19.

Foo CSY, Lechartier B, Kolly GS, Boy-Röttger S, Neres J, Rybniker J, Lupien A, Sala C, Piton J, Cole ST. 2016. Characterization of DprE1-mediated benzothiazinone resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 60(11):6451–6459. doi:10.1128/AAC.01523-16.

Hariguchi N, Chen X, Hayashi Y, Kawano Y, Fujiwara M, Matsuba M, Shimizu H, Ohba Y, Nakamura I, Kitamoto R, Shinohara T, Uematsu Y, Ishikawa S, Itotani M, Haraguchi Y, Takemura I, Matsumoto M. 2020. OPC-167832, a novel carbostyril derivative with potent antituberculosis activity as a DPRE1 inhibitor. Antimicrob. Agents Chemother. 64(6):e02020–19. doi:10.1128/AAC.02020-19.

Karoli T, Becker B, Zuegg J, Möllmann U, Ramu S, Huang JX, Cooper MA. 2012. Identification of antitubercular benzothiazinone compounds by ligandbased design. J. Med. Chem. 55(17):7940–7944. doi:10.1021/jm3008882.

Kim S, De Los Reyes V AA, Jung E. 2020. Countryspecific intervention strategies for top three TB burden countries using mathematical model. PLoS One 15(4):e0230964. doi:10.1371/journal.pone.0230964.

Kyu HH, Maddison ER, Henry NJ, Ledesma JR, Wiens KE, Reiner R, Biehl MH, Shields C, OsgoodZimmerman A, Ross JM, Carter A, Frank TD, Wang H, Srinivasan V, Abebe Z, Agarwal SK, Alahdab F, Alene KA, Ali BA, Alvis-Guzman N, Andrews JR, Antonio CAT, Atique S, Atre SR, Awasthi A, Ayele HT, Badali H, Badawi A, Barac A, Bedi N, Behzadifar M, Behzadifar M, Bekele BB, Belay SA, Bensenor IM, Butt ZA, Carvalho F, Cercy K, Christopher DJ, Daba AK, Dandona L, Dandona R, Daryani A, Demeke FM, Deribe K, Dharmaratne SD, Doku DT, Dubey M, Edessa D, El-Khatib Z, Enany S, Fernandes E, Fischer F, Garcia-Basteiro AL, Gebre AK, Gebregergs GB, Gebremichael TG, Gelano TF, Geremew D, Gona PN, Goodridge A, Gupta R, Bidgoli HH, Hailu GB, Hassen HY, Hedayati MT, Henok A, Hostiuc S, Hussen MA, Ilesanmi OS, Irvani SSN, Jacobsen KH, Johnson SC, Jonas JB, Kahsay A, Kant S, Kasaeian A, Kassa TD, Khader YS, Khafaie MA, Khalil I, Khan EA, Khang YH, Kim YJ, Kochhar S, Koyanagi A, Krohn KJ, Kumar GA, Lakew AM, Leshargie CT, Lodha R, MacArayan ERK, Majdzadeh R, Martins-Melo FR, Melese A, Memish ZA, Mendoza W, Mengistu DT, Mengistu G, Mestrovic T, Moazen B, Mohammad KA, Mohammed S, Mokdad AH, Moosazadeh M, Mousavi SM, Mustafa G, Nachega JB, Nguyen LH, Nguyen SH, Nguyen TH, Ningrum DNA, Nirayo YL, Nong VM, Ofori-Asenso R, Ogbo FA, Oh IH, Oladimeji O, Olagunju AT, Oren E, Pereira DM, Prakash S, Qorbani M, Rafay A, Rai RK, Ram U, Rubino S, Safiri S, Salomon JA, Samy AM, Sartorius B, Satpathy M, Seyedmousavi S, Sharif M, Silva JP, Silveira DGA, Singh JA, Sreeramareddy CT, Tran BX, Tsadik AG, Ukwaja KN, Ullah I, Uthman OA, Vlassov V, Vollset SE, Vu G, Weldegebreal F, Werdecker A, Yimer EM, Yonemoto N, Yotebieng M, Naghavi M, Vos T, Hay SI, Murray CJ. 2018. Global, regional, and national burden of tuberculosis, 1990-2016: Results from the global burden of diseases, injuries, and risk factors 2016 study. Lancet Infect. Dis. 18(12):1329–1349. doi:10.1016/S1473-3099(18)30625-X.

Laskowski RA, MacArthur MW, Moss DS, Thornton JM. 1993. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26(2):283–291. doi:10.1107/s0021889892009944.

Liu L, Kong C, Fumagalli M, Savková K, Xu Y, Huszár S, Sammartino JC, Fan D, Chiarelli LR, Mikušová K, Sun Z, Qiao C. 2020. Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents. Eur. J. Med. Chem. 208:112773. doi:10.1016/j.ejmech.2020.112773.

Maharaj Y, Bhakat S, Soliman M. 2015. Computeraided identification of novel DprE1 inhibitors as potential anti-TB lead compounds: A hybrid virtual-screening and molecular dynamics approach. Lett. Drug Des. Discovery 12(4):302–313. doi:10.2174/1570180811666141001005536.

Makarov V, Manina G, Mikusova K, Möllmann U, Ryabova O, Saint-Joanis B, Dhar N, Pasca MR, Buroni S, Lucarelli AP, Milano A, De Rossi E, Belanova M, Bobovska A, Dianiskova P, Kordulakova J, Sala C, Fullam E, Schneider P, McKinney JD, Brodin P, Christophe T, Waddell S, Butcher P, Albrethsen J, Rosenkrands I, Brosch R, Nandi V, Bharath S, Gaonkar S, Shandil RK, Balasubramanian V, Balganesh T, Tyagi S, Grosset J, Riccardi G, Cole ST. 2009. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324(5928):801–804. doi:10.1126/science.1171583.

Meshram RJ, Bagul KT, Pawnikar SP, Barage SH, Kolte BS, Gacche RN. 2020. Known compounds and new lessons: Structural and electronic basis of flavonoid-based bioactivities. J. Biomol. Struct. Dyn. 38(4):1168–1184. doi:10.1080/07391102.2019.1597770.

Neres J, Hartkoorn RC, Chiarelli LR, Gadupudi R, Pasca MR, Mori G, Venturelli A, Savina S, Makarov V, Kolly GS, Molteni E, Binda C, Dhar N, Ferrari S, Brodin P, Delorme V, Landry V, De Jesus Lopes Ribeiro AL, Farina D, Saxena P, Pojer F, Carta A, Luciani R, Porta A, Zanoni G, De Rossi E, Costi MP, Riccardi G, Cole ST. 2015. 2-carboxyquinoxalines kill Mycobacterium tuberculosis through noncovalent inhibition of DprE1. ACS Chem. Biol. 10(3):705– 714. doi:10.1021/cb5007163.

Oh S, Trifonov L, Yadav VD, Barry CE, Boshoff HI. 2021. Tuberculosis drug discovery: A aecade of hit assessment for defined targets. Front. Cell. Infect. Microbiol. 11:611304. doi:10.3389/fcimb.2021.611304.

Panda M, Ramachandran S, Ramachandran V, Shirude PS, Humnabadkar V, Nagalapur K, Sharma S, Kaur P, Guptha S, Narayan A, Mahadevaswamy J, Ambady A, Hegde N, Rudrapatna SS, Hosagrahara VP, Sambandamurthy VK, Raichurkar A. 2014. Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent antimycobacterial activity. J. Med. Chem. 57(11):4761– 4771. doi:10.1021/jm5002937.

Piton J, Foo CS, Cole ST. 2017. Structural studies of Mycobacterium tuberculosis DprE1 interacting with its inhibitors. doi:10.1016/j.drudis.2016.09.014.

Sterling T, Irwin JJ. 2015. ZINC 15 - Ligand discovery for everyone. J. Chem. Inf. Model. 55(11):2324–2337. doi:10.1021/acs.jcim.5b00559.

The UniProt Consortium. 2021. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res. 49(D1):D480–D489. doi:10.1093/nar/gkaa1100. Webb B, Sali A. 2021. Protein Structure Modeling with MODELLER. Methods Mol. Biol. 2199:1–15. doi:10.1007/978-1-0716-0892-0_14.

Wiederstein M, Sippl MJ. 2007. ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 35(SUPPL.2):W407–10. doi:10.1093/nar/gkm290.

Wilsey C, Gurka J, Toth D, Franco J. 2013. A large scale virtual screen of DprE1. Comput. Biol. Chem. 47:121–125. doi:https://doi.org/10.1016/j.compbiolchem.2013.08.006.

DOI: https://doi.org/10.22146/ijbiotech.80145