Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T01318 | Target Info | |||
| Target Name | Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase) | ||||
| Synonyms | PFF0160c; Mitochondrially bound dihydroorotate-ubiqui oxidoreductase; Dihydroorotate oxidase of Plasmodium falciparum; Dihydroorotate dehydrogenase of Plasmodium falciparum; DHOdehase of Plasmodium falciparum; DHODase; DHODH of Plasmodium falciparum; DHOD | ||||
| Target Type | Successful Target | ||||
| Gene Name | Malaria DHOdehase | ||||
| Biochemical Class | CH-CH donor oxidoreductase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Lauryl Dimethylamine-N-Oxide | Ligand Info | |||
| Canonical SMILES | CCCCCCCCCCCC[N+](C)(C)[O-] | ||||
| InChI | 1S/C14H31NO/c1-4-5-6-7-8-9-10-11-12-13-14-15(2,3)16/h4-14H2,1-3H3 | ||||
| InChIKey | SYELZBGXAIXKHU-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 15433 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 3I65 Plasmodium falciparum dihydroorotate dehydrogenase bound with triazolopyrimidine-based inhibitor DSM1 | ||||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [1] |
| PDB Sequence |
SYNPEFFLYD
169 IFLKFCLKYI179 DGEICHDLFL189 LLGKYNILPY199 DTSNDSIYAC209 TNIKHLDFIN 219 PFGVAAGFDK229 NGVCIDSILK239 LGFSFIEIGT249 ITPRGQTGNA259 KPRIFRDVES 269 RSIINSCGFN279 NMGCDKVTEN289 LILFRKRQEE299 DKLLSKHIVG309 VSIGKNKDTV 319 NIVDDLKYCI329 NKIGRYADYI339 AINVSSPNEA357 GKLKNIILSV367 KEEIDNLEKN 377 NIMNDEFLWF417 NTTKKKPLVF427 VKLAPDLNQE437 QKKEIADVLL447 ETNIDGMIIS 457 NTTTQINDIK467 SFENKKGGVS477 GAKLKDISTK487 FICEMYNYTN497 KQIPIIASGG 507 IFSGLDALEK517 IEAGASVCQL527 YSCLVFNGMK537 SAVQIKRELN547 HLLYQRGYYN 557 LKEAIGRKHS567
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| PDB ID: 3O8A Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with novel Inhibitor Genz667348 | ||||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [2] |
| PDB Sequence |
YNPEFFLYDI
170 FLKFCLKYID180 GEICHDLFLL190 LGKYNILPYD200 TSNDSIYACT210 NIKHLDFINP 220 FGVAAGFDKN230 GVCIDSILKL240 GFSFIEIGTI250 TPRGQTGNAK260 PRIFRDVESR 270 SIINSCGFNN280 MGCDKVTENL290 ILFRKRQEED300 KLLSKHIVGV310 SIGKNKDTVN 320 IVDDLKYCIN330 KIGRYADYIA340 INVSSPNTPG350 LRDNQEAGKL360 KNIILSVKEE 370 IDNLEKNNIM380 NDEFLWFNTT420 KKKPLVFVKL430 APDLNQEQKK440 EIADVLLETN 450 IDGMIISNTT460 TQINDIKSFE470 NKKGGVSGAK480 LKDISTKFIC490 EMYNYTNKQI 500 PIIASGGIFS510 GLDALEKIEA520 GASVCQLYSC530 LVFNGMKSAV540 QIKRELNHLL 550 YQRGYYNLKE560 AIGRK
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| PDB ID: 6E0B Plasmodium falciparum dihydroorotate dehydrogenase C276F mutant bound with triazolopyrimidine-based inhibitor DSM1 | ||||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | Yes | [3] |
| PDB Sequence |
NPEFFLYDIF
171 LKFCLKYIDG181 EICHDLFLLL191 GKYNILPYDT201 SNDSIYACTN211 IKHLDFINPF 221 GVAAGFDKNG231 VCIDSILKLG241 FSFIEIGTIT251 PRGQTGNAKP261 RIFRDVESRS 271 IINSFGFNNM281 GCDKVTENLI291 LFRKRQEEDK301 LLSKHIVGVS311 IGKNKDTVNI 321 VDDLKYCINK331 IGRYADYIAI341 NVSSPNTPGL351 RDNQEAGKLK361 NIILSVKEEI 371 DNLEKNNIMN381 DEFLWFNTTK421 KKPLVFVKLA431 PDLNQEQKKE441 IADVLLETNI 451 DGMIISNTTT461 QINDIKSFEN471 KKGGVSGAKL481 KDISTKFICE491 MYNYTNKQIP 501 IIASGGIFSG511 LDALEKIEAG521 ASVCQLYSCL531 VFNGMKSAVQ541 IKRELNHLLY 551 QRGYYNLKEA561 IGRKH
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| PDB ID: 5TBO Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421 | ||||||
| Method | X-ray diffraction | Resolution | 2.15 Å | Mutation | No | [4] |
| PDB Sequence |
NPEFFLYDIF
171 LKFCLKYIDG181 EICHDLFLLL191 GKYNILPYDT201 SNDSIYACTN211 IKHLDFINPF 221 GVAAGFDKNG231 VCIDSILKLG241 FSFIEIGTIT251 PRGQTGNAKP261 RIFRDVESRS 271 IINSCGFNNM281 GCDKVTENLI291 LFRKRQEEDK301 LLSKHIVGVS311 IGKNKDTVNI 321 VDDLKYCINK331 IGRYADYIAI341 NVEAGKLKNI363 ILSVKEEIDN373 LEKNNIMNDE 383 FLWFNTTKKK423 PLVFVKLAPD433 LNQEQKKEIA443 DVLLETNIDG453 MIISNTTTQI 463 NDIKSFENKK473 GGVSGAKLKD483 ISTKFICEMY493 NYTNKQIPII503 ASGGIFSGLD 513 ALEKIEAGAS523 VCQLYSCLVF533 NGMKSAVQIK543 RELNHLLYQR553 GYYNLKEAIG 563 RK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .LDA or .LDA2 or .LDA3 or :3LDA;style chemicals stick;color identity;select .A:163 or .A:164 or .A:167 or .A:168 or .A:171 or .A:195 or .A:196 or .A:197 or .A:198 or .A:199; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 5DEL Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM59 | ||||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [5] |
| PDB Sequence |
NPEFFLYDIF
171 LKFCLKYIDG181 EICHDLFLLL191 GKYNILPYDT201 SNDSIYACTN211 IKHLDFINPF 221 GVAAGFDKNG231 VCIDSILKLG241 FSFIEIGTIT251 PRGQTGNAKP261 RIFRDVESRS 271 IINSCGFNNM281 GCDKVTENLI291 LFRKRQEEDK301 LLSKHIVGVS311 IGKNKDTVNI 321 VDDLKYCINK331 IGRYADYIAI341 NVSSPNTPGL351 RDNQEAGKLK361 NIILSVKEEI 371 DNLEKNNIMN381 DEFLWFNTTK421 KKPLVFVKLA431 PDLNQEQKKE441 IADVLLETNI 451 DGMIISNTTT461 QINDIKSFEN471 KKGGVSGAKL481 KDISTKFICE491 MYNYTNKQIP 501 IIASGGIFSG511 LDALEKIEAG521 ASVCQLYSCL531 VFNGMKSAVQ541 IKRELNHLLY 551 QRGYYNLKEA561 IGRK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .LDA or .LDA2 or .LDA3 or :3LDA;style chemicals stick;color identity;select .A:164 or .A:199; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 5FI8 Crystal structure of plasmodium falciparum dihydroorotate dehydrogenase bounded with DSM422 (Tetrahydro-2-naphthyl and 2-indanyl triazolopyrimidine) | ||||||
| Method | X-ray diffraction | Resolution | 2.32 Å | Mutation | No | [6] |
| PDB Sequence |
NPEFFLYDIF
171 LKFCLKYIDG181 EICHDLFLLL191 GKYNILPYDT201 SNDSIYACTN211 IKHLDFINPF 221 GVAAGFDKNG231 VCIDSILKLG241 FSFIEIGTIT251 PRGQTGNAKP261 RIFRDVESRS 271 IINSCGFNNM281 GCDKVTENLI291 LFRKRQEEDK301 LLSKHIVGVS311 IGKNKDTVNI 321 VDDLKYCINK331 IGRYADYIAI341 NVQEAGKLKN362 IILSVKEEID372 NLEKNNIMND 382 EFLWFNTTKK422 KPLVFVKLAP432 DLNQEQKKEI442 ADVLLETNID452 GMIISNTTTQ 462 INDIKSFENK472 KGGVSGAKLK482 DISTKFICEM492 YNYTNKQIPI502 IASGGIFSGL 512 DALEKIEAGA522 SVCQLYSCLV532 FNGMKSAVQI542 KRELNHLLYQ552 RGYYNLKEAI 562 GRK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .LDA or .LDA2 or .LDA3 or :3LDA;style chemicals stick;color identity;select .A:164 or .A:167 or .A:168 or .A:171 or .A:195 or .A:196 or .A:197 or .A:198 or .A:199 or .A:239; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds. J Biol Chem. 2009 Sep 25;284(39):26999-7009. | ||||
| REF 2 | Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model. J Biol Chem. 2010 Oct 22;285(43):33054-33064. | ||||
| REF 3 | Identification and Mechanistic Understanding of Dihydroorotate Dehydrogenase Point Mutations in Plasmodium falciparum that Confer in Vitro Resistance to the Clinical Candidate DSM265. ACS Infect Dis. 2019 Jan 11;5(1):90-101. | ||||
| REF 4 | A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. ACS Infect Dis. 2016 Dec 9;2(12):945-957. | ||||
| REF 5 | The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions. Acta Crystallogr F Struct Biol Commun. 2015 May;71(Pt 5):553-9. | ||||
| REF 6 | Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity. J Med Chem. 2016 Jun 9;59(11):5416-31. | ||||
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