Many compounds can cause liver injury, after oral administration the first major organ exposed is the liver. The LiverTox is a database of information on the diagnosis, cause, frequency, patterns, and management of liver injury attributable to prescription and nonprescription medications, herbals and dietary supplements.

Checking for the potential to cause liver injury is an important part of the drug discovery process and there are a number of in vitro and in vivo assays that can be used.

High dose studies in safety species are undertaken to identify potential toxicities and to determine safety margins, Clinically, the most relevant reactions include liver necrosis, hepatitis, cholestasis, vascular changes and steatosis. A drug can cause liver toxicity via multiple mechanisms, it can be the result of a direct action of the parent compound or indirectly through reactive metabolites. The drug or its metabolites may cause liver toxicity after specific receptor binding, or reactive metabolites can react with hepatic macromolecules, all leading to direct cytotoxicity. In addition, Immune-mediated idiosyncratic drug reaction has been responsible for numerous serious hepatotoxic events in humans

It would be useful to be able to predict ahead of synthesis whether a molecule was likely to cause liver injury and that is the function of DILIpredictor DOI. Using data form several thousand molecules and a variety of different assays (both in vitro and in vivo) and different species the authors have developed a predictive model. The attraction of this approach is in addition to giving an early flag of potential DILI it also highlights potential species differences and can give an insight into the mechanism.

DILIPredictor required only chemical structures as input for prediction and is publicly available at https://broad.io/DILIPredictor for use via web interface (please don't submit confidential molecules) and with all code available for download from GitHub

https://github.com/srijitseal/DILI_Predictor

I installed like this since it currently does not run with the latest version of python

conda create -n DILIpred python=3.10
conda activate DILIpred

pip install DILIpred

It can then beinstalled as follows.

conda create -n DILIpred python=3.10
conda activate DILIpred

pip install DILIpred

It can then be usef as follows

(DILIpred) chrisswain@Mac-Studio ~ % dilipred -smiles "C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C"

If you use DILIPred in your work, please cite: Improved Detection of Drug-Induced Liver Injury by Integrating Predicted In Vivo and In Vitro Data Srijit Seal, Dominic Williams, Layla Hosseini-Gerami, Manas Mahale, Anne E. Carpenter, Ola Spjuth, and Andreas Bender doi: https://doi.org/10.1021/acs.chemrestox.4c00015

100%███████████████████████████████████████████████████████████████ 1/1 [00:01<00:00, 1.14s/it] 2024-07-12 08:29:44.777 | CRITICAL | dilipred.main:predict:458 - The compound is predicted DILI-Positive

The detailed output is contained in a file created.

source,assaytype,description,value,pred,SHAP contribution to Toxicity,SHAP,smiles,smilesr DILI,DILIstFDA,This is the predicted FDA DILIst label,0.8187885151383966,1,N/A,N/A,C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C= C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O)c2ccc(F)cc2)C3C)n1 Diverse DILI C,Heterogenous Data ,"Transient liver function abnormalities, adverse hepatic effects",0.7393781727510759,True,Positive,0.003926801602711443,C[C@@H] 1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O )c2ccc(F)cc2)C3C)n1 BESP,Mechanisms of Liver Toxicity,BESP Bile Salt Export Pump Inhibition,0.5655727513227511,True,Positive,0.0003070244326849143,C[C@@H ]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(= O)c2ccc(F)cc2)C3C)n1 Mitotox,Mechanisms of Liver Toxicity,Mitotox ,0.10973983865879627,False,Positive,0.0006130947805277731,C[C@@H]1C2=NN= C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O)c2ccc( F)cc2)C3C)n1 Reactive Metabolite,Mechanisms of Liver Toxicity,Reactive Metabolite Formation,0.19967540492325553,False,Negative,-0.001048102741727997,C[C@@ H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C( =O)c2ccc(F)cc2)C3C)n1 Human hepatotoxicity,Human hepatotoxicity,"Human hepatotoxicity, hepatobiallry",0.7196576912119554,True,Positive,0.007802364907899422,C[C @@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN( C(=O)c2ccc(F)cc2)C3C)n1 Animal hepatotoxicity A,Animal hepatotoxicity,"Rat, chronic oral administration, Hepatic histopathologic effects, ToxRefDB",0.5867747455286331,True,Positive,0.0030731971130978854,C[C@@H] 1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O )c2ccc(F)cc2)C3C)n1 Animal hepatotoxicity B,Animal hepatotoxicity,"Hepatocellular hypertrophy, rats, ORAD, HESS",0.6646590439473917,True,Positive,0.0013360236463188587,C[C@@H]1C2= NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O) c2ccc(F)cc2)C3C)n1 Preclinical hepatotoxicity,Animal hepatotoxicity,"Preclinical hepatotoxicity data from PharmaPendium, Leadscopre, and internal repository with 14- to 28-day rat study data",0.8576928962241468,True,Positive,0.011692057666492625,C[C@@H]1C2= NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O) c2ccc(F)cc2)C3C)n1 Diverse DILI A,Heterogenous Data ,Large-scale and diverse ddrug induced liver injury dataset,0.6324274304660036,True,Positive,0.003398315762493277,C[C@@H]1C2 =NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O) c2ccc(F)cc2)C3C)n1 source,assaytype,description,value,pred,SHAP contribution to Toxicity,SHAP,smiles,smilesr DILI,DILIstFDA,This is the predicted FDA DILIst label,0.8187885151383966,1,N/A,N/A,C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C= C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O)c2ccc(F)cc2)C3C)n1 Diverse DILI C,Heterogenous Data ,"Transient liver function abnormalities, adverse hepatic effects",0.7393781727510759,True,Positive,0.003926801602711443,C[C@@H] 1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O )c2ccc(F)cc2)C3C)n1 BESP,Mechanisms of Liver Toxicity,BESP Bile Salt Export Pump Inhibition,0.5655727513227511,True,Positive,0.0003070244326849143,C[C@@H ]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(= O)c2ccc(F)cc2)C3C)n1 Mitotox,Mechanisms of Liver Toxicity,Mitotox ,0.10973983865879627,False,Positive,0.0006130947805277731,C[C@@H]1C2=NN= C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O)c2ccc( F)cc2)C3C)n1 Reactive Metabolite,Mechanisms of Liver Toxicity,Reactive Metabolite Formation,0.19967540492325553,False,Negative,-0.001048102741727997,C[C@@ H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C( =O)c2ccc(F)cc2)C3C)n1 Human hepatotoxicity,Human hepatotoxicity,"Human hepatotoxicity, hepatobiallry",0.7196576912119554,True,Positive,0.007802364907899422,C[C @@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN( C(=O)c2ccc(F)cc2)C3C)n1 Animal hepatotoxicity A,Animal hepatotoxicity,"Rat, chronic oral administration, Hepatic histopathologic effects, ToxRefDB",0.5867747455286331,True,Positive,0.0030731971130978854,C[C@@H] 1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O )c2ccc(F)cc2)C3C)n1 Animal hepatotoxicity B,Animal hepatotoxicity,"Hepatocellular hypertrophy, rats, ORAD, HESS",0.6646590439473917,True,Positive,0.0013360236463188587,C[C@@H]1C2= NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O) c2ccc(F)cc2)C3C)n1 Preclinical hepatotoxicity,Animal hepatotoxicity,"Preclinical hepatotoxicity data from PharmaPendium, Leadscopre, and internal repository with 14- to 28-day rat study data",0.8576928962241468,True,Positive,0.011692057666492625,C[C@@H]1C2= NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O) c2ccc(F)cc2)C3C)n1 Diverse DILI A,Heterogenous Data ,Large-scale and diverse ddrug induced liver injury dataset,0.6324274304660036,True,Positive,0.003398315762493277,C[C@@H]1C2 =NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C,Cc1nsc(-c2nnc3n2CCN(C(=O) c2ccc(F)cc2)C3C)n1

Overall a useful tool to have to hand.