3TIK
Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the tipifarnib derivative 6-((4-chlorophenyl)(methoxy)(1-methyl-1H-imidazol-5-yl)methyl)-4-(2,6-difluorophenyl)-1-methylquinolin-2(1H)-one
Summary for 3TIK
| Entry DOI | 10.2210/pdb3tik/pdb |
| Related | 3g1q |
| Descriptor | sterol 14-alpha demethylase (CYP51), PROTOPORPHYRIN IX CONTAINING FE, 6-[(R)-(4-chlorophenyl)(methoxy)(1-methyl-1H-imidazol-5-yl)methyl]-4-(2,6-difluorophenyl)-1-methylquinolin-2(1H)-one, ... (4 entities in total) |
| Functional Keywords | sterol 14-alpha demethylase, cyp51, heme, monooxygenase, sterol biosynthesis, cytochrome p450 fold, oxidoreductase, cytochrome p450 reductase, endoplasmic reticulum membrane |
| Biological source | Trypanosoma brucei |
| Total number of polymer chains | 4 |
| Total formula weight | 209700.00 |
| Authors | Hargrove, T.Y.,Wawrzak, Z.,Kraus, J.M.,Gelb, M.H.,Buckner, F.S.,Waterman, M.R.,Lepesheva, G.I. (deposition date: 2011-08-20, release date: 2012-07-11, Last modification date: 2023-09-13) |
| Primary citation | Buckner, F.S.,Bahia, M.T.,Suryadevara, P.K.,White, K.L.,Shackleford, D.M.,Chennamaneni, N.K.,Hulverson, M.A.,Laydbak, J.U.,Chatelain, E.,Scandale, I.,Verlinde, C.L.,Charman, S.A.,Lepesheva, G.I.,Gelb, M.H. Pharmacological characterization, structural studies, and in vivo activities of anti-chagas disease lead compounds derived from tipifarnib. Antimicrob.Agents Chemother., 56:4914-4921, 2012 Cited by PubMed Abstract: Chagas disease, caused by the protozoan pathogen Trypanosoma cruzi, remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14α-demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas disease drugs. Posaconazole is under clinical investigation for Chagas disease, although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor tipifarnib has potent anti-T. cruzi activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT-inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to that of posaconazole in a murine model of T. cruzi infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than that of the tipifarnib analog after repeat twice-daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported here and provides new insights to guide structure-based drug design for further optimized compounds. PubMed: 22777048DOI: 10.1128/AAC.06244-11 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
Download full validation report
