Establishment of an &lt;i&gt;in silico&lt;/i&gt; phototoxicity prediction method by combining descriptors related to photo-absorption and photo-reaction

Haranosono, Yu; Kurata, Masahiro; Sakaki, Hideyuki

doi:10.2131/jts.39.655

Cited by 19 publications

(21 citation statements)

References 16 publications

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“…In a previous report, we introduced a descriptor-based method for phototoxicity prediction (Haranosono et al, 2014). In this study, we illustrated that this methodology can be adapted for PLD prediction by combining three descriptors.…”

Section: Discussionmentioning

confidence: 92%

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Establishment of an <i>in silico</i> phospholipidosis prediction method using descriptors related to molecular interactions causing phospholipid–compound complex formation

et al. 2016

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-Although phospholipidosis (PLD) often affects drug development, there is no convenient in vitro or in vivo test system for PLD detection. In this study, we developed an in silico PLD prediction method based on the PLD-inducing mechanism. We focused on phospholipid (PL)-compound complex formation, which inhibits PL degradation by phospholipase. Thus, we used some molecular interactions, such as electrostatic interactions, hydrophobic interactions, and intermolecular forces, between PL and compounds as descriptors. First, we performed descriptor screening for intermolecular force and then developed a new in silico PLD prediction using descriptors related to molecular interactions. Based on the screening, we identified molecular refraction (MR) as a descriptor of intermolecular force. It is known that ClogP and most-basic pKa can be used for PLD prediction. Thereby, we developed an in silico prediction method using ClogP, most-basic pKa, and MR, which were related to hydrophobic interactions, electrostatic interactions, and intermolecular forces. In addition, a resampling method was used to determine the cut-off values for each descriptor. We obtained good results for 77 compounds as follows: sensitivity = 95.8%, specificity = 75.9%, and concordance = 88.3%. Although there is a concern regarding false-negative compounds for pKa calculations, this predictive ability will be adequate for PLD screening.In conclusion, the mechanism-based in silico PLD prediction method provided good prediction ability, and this method will be useful for evaluating the potential of drugs to cause PLD, particularly in the early stage of drug development, because this method only requires knowledge of the chemical structure.

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Section: Discussionmentioning

confidence: 92%

“…method to set the cut-off line in a similar manner as an in silico prediction tool for phototoxicity (Haranosono et al, 2014), and there is knowledge of a mutagenicity prediction method using a similar algorithm (Yuta, 2010).…”

Section: Establishment Of An In Silico Pld Prediction Methodsmentioning

confidence: 99%

Establishment of an <i>in silico</i> phospholipidosis prediction method using descriptors related to molecular interactions causing phospholipid–compound complex formation

et al. 2016

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“…HOMO-LUMO energy gap (HL-gap) was reported as a predictive factor for phototoxicity, and large HL-gap would contribute to prevent excitation of compounds by light. 8 We therefore explored bicyclic aromatic rings with an increased HL-gap relative to 1. HUMO and LUMO orbital energy of the energy-minimized conformation of compound was used to calculate HL-gap.…”

Section: Resultsmentioning

confidence: 99%

“…Although we reported that compound 2 was metabolically unstable in human microsomes, 6s it had no phototoxicity in the 3T3 NRU test (MPE value = 0.00), suggesting that the long p-system of quinolinyl phenyl moiety of compound 1 is a major cause for phototoxicity. 8 Attenuation of phototoxicity was therefore assumed to be achieved by changing quinolinyl phenyl moiety of lead compound 1.…”

Section: Introductionmentioning

confidence: 99%

Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436

Hamaguchi

Masuda

Miyamoto

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Previously, we have reported an in silico prediction method for in vitro 3T3 NRU-PT phototoxicity (Haranosono et al, 2014). Our in silico method was established with 2 descriptors; i.e., π electron number (PEN) and HOMO-LUMO Gap (HLG), which are related to photo-absorption and photochemical reaction, respectively.…”

Section: Introductionmentioning

confidence: 99%

A study for finding new phototoxicity descriptors related to potential energy

Haranosono

Nemoto

Kurata

et al. 2017

Fundam. Toxicol. Sci.

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-It is known that phototoxicity is related to chemical structure. We have previously reported a prediction method of chemical structure-based in silico phototoxicity for in vitro 3T3 NRU-PT assay. To improve the concordance of the method, here we added new descriptors related to another mechanism of phototoxicity. We focused on potential energy, which certainly contributes to chemical reactivity regardless of photo-irradiation. As a result, stretch-bend, a form of potential energy, was found as a new descriptor of phototoxicity. Our analysis strongly indicates that chemical reactivity is an important factor for phototoxic outcome.

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Establishment of an <i>in silico</i> phototoxicity prediction method by combining descriptors related to photo-absorption and photo-reaction

Cited by 19 publications

References 16 publications

Establishment of an <i>in silico</i> phospholipidosis prediction method using descriptors related to molecular interactions causing phospholipid–compound complex formation

Establishment of an <i>in silico</i> phospholipidosis prediction method using descriptors related to molecular interactions causing phospholipid–compound complex formation

Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436

A study for finding new phototoxicity descriptors related to potential energy

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