6GEQ
Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP121A1 in complex with Triazole Pyrazole inhibitor 14a
Summary for 6GEQ
| Entry DOI | 10.2210/pdb6geq/pdb |
| Descriptor | Mycocyclosin synthase, PROTOPORPHYRIN IX CONTAINING FE, 1-phenyl-3-pyridin-4-yl-~{N}-(pyridin-4-ylmethyl)pyrazole-4-carboxamide, ... (5 entities in total) |
| Functional Keywords | inhibitor complex p450, antibiotic, oxidoreductase |
| Biological source | Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh) |
| Total number of polymer chains | 1 |
| Total formula weight | 44469.87 |
| Authors | Levy, C.W. (deposition date: 2018-04-27, release date: 2019-08-07, Last modification date: 2024-01-17) |
| Primary citation | Kishk, S.M.,McLean, K.J.,Sood, S.,Smith, D.,Evans, J.W.D.,Helal, M.A.,Gomaa, M.S.,Salama, I.,Mostafa, S.M.,de Carvalho, L.P.S.,Levy, C.W.,Munro, A.W.,Simons, C. Design and Synthesis of Imidazole and Triazole Pyrazoles asMycobacterium TuberculosisCYP121A1 Inhibitors. Chemistryopen, 8:995-1011, 2019 Cited by PubMed Abstract: The emergence of untreatable drug-resistant strains of is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. cytochrome P450 CYP121A1 is a promising drug target for the treatment of tuberculosis owing to its essential role in mycobacterial growth. Using a rational approach, which includes molecular modelling studies, three series of azole pyrazole derivatives were designed through two synthetic pathways. The synthesized compounds were biologically evaluated for their inhibitory activity towards and their protein binding affinity ( ). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl () and -butyl () compounds displaying optimal activity (MIC 1.562 μg/mL, 0.22 μM () and 4.81 μM ()). The spectroscopic data showed that all the synthesised compounds produced a type II red shift of the heme Soret band indicating either direct binding to heme iron or (where less extensive Soret shifts are observed) putative indirect binding via an interstitial water molecule. Evaluation of biological and physicochemical properties identified the following as requirements for activity: LogP >4, H-bond acceptors/H-bond donors 4/0, number of rotatable bonds 5-6, molecular volume >340 Å, topological polar surface area <40 Å. PubMed: 31367508DOI: 10.1002/open.201900227 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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