6geq

Crystal structure of Mycobacterium tuberculosis cytochrome P450 CYP121A1 in complex with Triazole Pyrazole inhibitor 14a

spinqualitylabelsall models 6geq, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6geq is a 1 chain structure with sequence from Mycto. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EW5, HEM, SO4 Gene: cyp121, MT2336 (MYCTO) Activity: Mycocyclosin synthase, with EC number 1.14.21.9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CP121_MYCTO] Catalyzes C-C bond formation between the carbons ortho to the phenolic hydroxyl of cyclo(L-tyr-L-tyr) (cYY) producing mycocyclosin. Can also use cyclo(L-Tyr-L-Phe) (cYF), cyclo(L-Tyr-L-Trp) (cYW) and cyclo(L-Tyr-L-3,4-dihydroxyphenylalanine) (cY-DOPA) as substrate (By similarity). Publication Abstract from PubMed The emergence of untreatable drug-resistant strains of Mycobacterium tuberculosis is a major public health problem worldwide, and the identification of new efficient treatments is urgently needed. Mycobacterium tuberculosis 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 M. tuberculosis and their protein binding affinity (K D). Series 3 biarylpyrazole imidazole derivatives were the most effective with the isobutyl (10 f) and tert-butyl (10 g) compounds displaying optimal activity (MIC 1.562 mug/mL, K D 0.22 muM (10 f) and 4.81 muM (10 g)). 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 A(3), topological polar surface area <40 A(2). Design and Synthesis of Imidazole and Triazole Pyrazoles as Mycobacterium Tuberculosis CYP121A1 Inhibitors.,Kishk SM, McLean KJ, Sood S, Smith D, Evans JWD, Helal MA, Gomaa MS, Salama I, Mostafa SM, de Carvalho LPS, Levy CW, Munro AW, Simons C ChemistryOpen. 2019 Jul 23;8(7):995-1011. doi: 10.1002/open.201900227., eCollection 2019 Jul. PMID:31367508 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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