SMARTCyp 3.0: enhanced cytochrome P450 site-of-metabolism prediction server

Olsen, Lars; Montefiori, Marco; Tran, Khanhvi Phuc; Jørgensen, Flemming Steen

doi:10.1093/bioinformatics/btz037

Cited by 63 publications

(45 citation statements)

References 10 publications

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“…We note that our suggestions for the site of drug oxidation are only based on weakest bonds that do not explicitly account for accessibility of sites to the enzyme. These predictions could be further enhanced by incorporating accessibilities scores 52,53 .…”

Section: Development Of a Graph Neural Network For Predicting Bdementioning

confidence: 99%

Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with sub-second computational cost

et al. 2020

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Bond dissociation enthalpies (BDEs) of organic molecules play a fundamental role in determining chemical reactivity and selectivity. However, BDE computations at sufficiently high levels of quantum mechanical theory require substantial computing resources. In this paper, we develop a machine learning model capable of accurately predicting BDEs for organic molecules in a fraction of a second. We perform automated density functional theory (DFT) calculations at the M06-2X/def2-TZVP level of theory for 42,577 small organic molecules, resulting in 290,664 BDEs. A graph neural network trained on a subset of these results achieves a mean absolute error of 0.58 kcal mol −1 (vs DFT) for BDEs of unseen molecules. We further demonstrate the model on two applications: first, we rapidly and accurately predict major sites of hydrogen abstraction in the metabolism of drug-like molecules, and second, we determine the dominant molecular fragmentation pathways during soot formation.

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Section: Development Of a Graph Neural Network For Predicting Bdementioning

confidence: 99%

Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with sub-second computational cost

et al. 2020

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“…in the metabolism of imrecoxib in humans 27 , leading to an unique [+2O-2H] species having m/z = 361. This brief discussion applies primarily to radical reactivity in the absence of a protein environment, so to help better determine which compounds might be most likely to form due to mammalian CYP450 action-to guide our synthesis and testing program-we used three computer programs [28][29][30] that utilize known P450 reactivity data, to suggest the most likely positions for oxidations that would help explain formation of the stable m/z = 195, 347 (+1O); 361 (+2O-2H); 363 (+2O); 377 (+3O-2H); 377 [+3O-2H] and 379 [+3O] ions we see experimentally. The predictions also suggest which compounds would form and then decompose to other metabolites, with both stable SQ109 metabolites as well as SQ109 breakdown-products potentially having activity in cells.…”

Section: Resultsmentioning

confidence: 99%

Structure, in Vivo Detection and Anti-Bacterial Activity of Metabolites of SQ109, an Anti-Infective Drug Candidate

Malwal¹,

Zimmerman²,

Álvarez³

et al. 2021

Preprint

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SQ109 is a drug candidate for the treatment of tuberculosis (TB). It is thought to target primarily the protein MmpL3 in Mycobacterium tuberculosis, but it also inhibits the growth of some other bacteria, as well as fungi and protozoa. SQ109 is metabolized by the liver, and it has been proposed that some of its metabolites might be responsible for its activity against TB. Here, we synthesized six potential P450 metabolites of SQ109 and used these as well as 10 other likely metabolites as standards in a mass spectrometry study of M. tuberculosis-infected rabbits treated with SQ109, in addition to testing all 16 putative metabolites for anti-bacterial activity. We found that there were just two major metabolites in lung tissue: a hydroxy-adamantyl analog of SQ109 and N’-adamantylethylenediamine. Neither of these, or the other potential metabolites tested, inhibited the growth of M. tuberculosis, or of M. smegmatis, Bacillus subtilis or E. coli, making it unlikely that an SQ109 metabolite contributes to its anti-bacterial activity. In the rabbit TB model, it is thus the gradual accumulation of non-metabolized SQ109 in tissues to therapeutic levels that leads to good efficacy. Our results also provide new insights into how SQ109 binds to its target MmpL3, based on our mass spectroscopy results which indicate that the charge in SQ109 is primarily localized on the geranyl nitrogen, explaining the very short distance to a key Asp found in the X-ray structure of SQ109 bound to MmpL3. Our results also suggest that it is intact SQ109 that is likely to target some of the other bacteria, fungi and protozoa in which MmpL3-like proteins have recently been reported.

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“…71 Devising a similar comprehensive database of plant P450 families and subfamilies endowing herbicide metabolism would provide an excellent repertoire of information on their complex role in crop herbicide selectivity and weed resistance. Meanwhile, attempts to predict P450-mediated drug metabolism also have been made, such as SMARTCyp (https://smartcyp.sund.ku.dk/mol_to_som) 72 and FAME3 (https://nerdd.zbh.uni-hamburg.de/fame3/). 73 These provide P450s in weed management www.soci.org a fast prediction of P450 reactivity for drug metabolism.…”

Section: Challenges and Prospects On P450-mediated Herbicide Metabolimentioning

confidence: 99%

Cytochrome P450‐mediated herbicide metabolism in plants: current understanding and prospects

Dimaano

Iwakami

2020

Pest Management Science

113

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Cytochrome P450s (P450s) have been at the center of herbicide metabolism research as a result of their ability to endow selectivity in crops and resistance in weeds. In the last 20 years, ≈30 P450s from diverse plant species have been revealed to possess herbicide-metabolizing function, some of which were demonstrated to play a key role in plant herbicide sensitivity. Recent research even demonstrated that some P450s from crops and weeds metabolize numerous herbicides from various chemical backbones, which highlights the importance of P450s in the current agricultural systems. However, due to the enormous number of plant P450s and the complexity of their function, expression and regulation, it remains a challenge to fully explore the potential of P450-mediated herbicide metabolism in crop improvement and herbicide resistance mitigation. Differences in the substrate specificity of each herbicide-metabolizing P450 are now evident. Comparisons of the substrate specificity and protein structures of P450s will be beneficial for the discovery of selective herbicides and may lead to the development of crops with higher herbicide tolerance by transgenics or genome-editing technologies. Furthermore, the knowledge will help design sound management strategies for weed resistance including the prediction of cross-resistance patterns. Overcoming the ambiguity of P450 function in plant xenobiotic pathways will unlock the full potential of this enzyme family in advancing global agriculture and food security.

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SMARTCyp 3.0: enhanced cytochrome P450 site-of-metabolism prediction server

Cited by 63 publications

References 10 publications

Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with sub-second computational cost

Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with sub-second computational cost

Structure, in Vivo Detection and Anti-Bacterial Activity of Metabolites of SQ109, an Anti-Infective Drug Candidate

Cytochrome P450‐mediated herbicide metabolism in plants: current understanding and prospects

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