Corrigendum: Substrate Fragmentation for the Design of <i>M. tuberculosis</i> CYP121 Inhibitors

Kavanagh, Madeline E.; Gray, Janine L.; Gilbert, Sophie H.; Coyne, Anthony G.; McLean, Kirsty J.; Davis, Holly J.; Munro, Andrew W.; Abell, Chris

doi:10.1002/cmdc.201600619

Cited by 2 publications

(3 citation statements)

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“…However, at present we cannot conclude definitively that the activity against Mtb results from inhibition of CYP121A1. Binding affinity in the low lM range against CYP121A1 has been reported by Fonvielle et al 9 for cYY derivatives and by Hudson et al 23,24 for small fragment heterocyclic inhibitors. However, no inhibitory activity (i.e.…”

Section: Discussionmentioning

confidence: 71%

Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

El-wahab

Accietto

Mariño

et al. 2018

Bioorganic & Medicinal Chemistry

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Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH-imidazole or CH-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 Å. A model generated from a 1.5 Å crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.

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Section: Discussionmentioning

confidence: 71%

Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

El-wahab

Accietto

Mariño

et al. 2018

Bioorganic & Medicinal Chemistry

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“…Despite being structurally different, there was evidence of CYP121 haem group interaction, as with azole antifungals. This finding was very interesting, potentially indicating a new mechanism of drug action [43].…”

Section: Peptides Targeting Tuberculosismentioning

confidence: 77%

“…Taking this into account, Kavanagh and colleagues (2016) designed compounds for inhibiting the mycobacterial CYP121. The authors observed CYP121's affinity to di-indole dipeptide mimetics ( Figure 14), suggesting that tryptophan dipeptides are crucial [43][44][45][46][47][48]. From molecular fragments of cyclopeptides, derivatives containing indole as a pharmacophore were also developed.…”

Section: Peptides Targeting Tuberculosismentioning

confidence: 99%

Neglected tropical diseases and infectious illnesses: potential targeted peptides employed as hits compounds in drug design

Silva

Santos

Miranda

et al. 2020

Journal of Drug Targeting

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Neglected Tropical Diseases (NTDs) and infectious illnesses, such as malaria, tuberculosis and Zika fever, represent a major public health concern in many countries and regions worldwide, especially in developing ones. They cause thousands of deaths per year, and certainly compromise the life of affected patients. The drugs available for therapy are toxic, have considerable adverse effects, and are obsolete, especially with respect to resistance. In this context, targeted peptides are considered promising in the design of new drugs, since they have specific action and reduced toxicity. Indeed, there is a rising interest in these targeted compounds within the pharmaceutical industry, proving their importance to the Pharmaceutical Sciences field. Many have been approved by the Food and Drug Administration (FDA) to be used as medicines, plus there are more than 300 peptides currently in clinical trials. The main purpose of this review is to show the most promising potential targeted peptides acting as hits molecules in NTDs and other infectious illnesses. We hope to contribute to the discovery of medicines in this relatively neglected area, which will be extremely useful in improving the health of many suffering people.

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Corrigendum: Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors

Cited by 2 publications

References 0 publications

Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics

Neglected tropical diseases and infectious illnesses: potential targeted peptides employed as hits compounds in drug design

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