The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D

Crowley, Patrick; Berry, Edward A.; Cromartie, Thomas H.; Daldal, Fevzi; Godfrey, Christopher R. A.; Lee, Dong Woo; Phillips, Janet E.; Taylor, Anne; Viner, Russell

doi:10.1016/j.bmc.2008.10.030

Cited by 38 publications

(32 citation statements)

References 26 publications

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“…Acid binding is most likely hampered due to repulsive interactions with Glu-272. This prediction is supported by the previously published observation that the ester of crocasin, which resembles the lactone form of statins, but not the acid form, can bind to the Q o site of CIII (Crowley et al, 2008).…”

Section: Statin Lactones Specifically Inhibit the Enzymatic Activity Of CIII Of The Respiratory Chainsupporting

confidence: 74%

Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Schirris

Renkema

Ritschel³

et al. 2015

Cell Metabolism

198

170

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Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies.

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Section: Statin Lactones Specifically Inhibit the Enzymatic Activity Of CIII Of The Respiratory Chainsupporting

confidence: 74%

Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Schirris

Renkema

Ritschel³

et al. 2015

Cell Metabolism

198

170

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“…1 Recent crystallographic data suggest that the crocacins are a new class of inhibitors of the cytochrome bc 1 complex. 2 …”

mentioning

confidence: 99%

Enantioselective Synthesis of (+)-Crocacin C. An Example of a Highly Challenging Mismatched Double Asymmetric δ-Stannylcrotylboration Reaction

Chen

Roush

2012

Org. Lett.

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A concise, enantioselective synthesis of (+)-crocacin C is described, featuring a highly diastereoselective mismatched double asymmetric δ-stannylcrotylboration of the stereochemically demanding chiral aldehyde 9 with the bifunctional crotylborane reagent (S)-E-10. The total synthesis of (+)-crocacin C was accomplished in seven steps (longest linear sequence) starting from commercially available precursors.

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“…Crowley and coworkers [ 51 ] studied the binding of crocacins to the active site in order to design structurally simpler and more stable synthetic analogs. An inhibitor binding model to the mammalian cytochrome bc1 complex was constructed, which was consistent with X-ray crystallographic analysis of an analog bound to the chicken heart cytochrome bc1 complex.…”

Section: Other Natural Products Inhibiting the Cytochrome Bc1 Compmentioning

confidence: 99%

Natural Compound-Derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

2020

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The high incidence of fungal pathogens has become a global issue for crop protection. A promising strategy to control fungal plant infections is based on the use of nature-inspired compounds. The cytochrome bc1 complex is an essential component of the cellular respiratory chain and is one of the most important fungicidal targets. Natural products have played a crucial role in the discovery of cytochrome bc1 inhibitors, as proven by the development of strobilurins, one of the most important classes of crop-protection agents, over the past two decades. In this review, we summarize advances in the exploration of natural product scaffolds for the design and development of new bc1 complex inhibitors. Particular emphasis is given to molecular modeling-based approaches and structure–activity relationship (SAR) studies performed to improve the stability and increase the potency of natural precursors. The collected results highlight the versatility of natural compounds and provide an insight into the potential development of nature-inspired derivatives as antifungal agents.

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The role of molecular modeling in the design of analogues of the fungicidal natural products crocacins A and D

Cited by 38 publications

References 26 publications

Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition

Enantioselective Synthesis of (+)-Crocacin C. An Example of a Highly Challenging Mismatched Double Asymmetric δ-Stannylcrotylboration Reaction

Natural Compound-Derived Cytochrome bc1 Complex Inhibitors as Antifungal Agents

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