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Artificial Intelligence in Health New drug discovery in the AI era

Figure 1. Classical drug discovery and pre-clinical development flow
Abbreviations: MOA: Mechanism of action; NCE: New chemical entity; DMPK: Drug metabolism and pharmacokinetics; ADME: Absorption, distribution,
metabolism, and excretion; CYP: Cytochrome P450; PD: Pharmacodynamics; PPB: Plasma protein binding; BA: Bioanalytical; MD: Method development;
MV: Method validation; GLP: Good laboratory practice; MTD: Maximum tolerable dose; DRF: Dose range finding; hERG: human Ether-à-go-go-related
gene; FaSSIF: Fasted state simulated intestinal fluid; FeSSIF: Fed state simulated intestinal fluid; FaSSGF: Fasted state simulated gastric fluid.

2.2. Toxicity-driven phase IV withdrawals necrosis, and alterations in hepatic enzyme levels. 11-14 It is
Unexpected toxicity is the primary reason for drug dropouts the leading cause of post-market withdrawals of approved
not only during clinical trials but also in post-marketing drugs such as troglitazone, tolcapone, trovafloxacin,
[Phase IV] withdrawals. It is nearly impossible to predict bromfenac, nefazodone, ximelagatran, lumiracoxib, and
drug safety and toxicity with confidence even in late-stage sitaxentan. Acetaminophen is the second-most frequent
development, as rare adverse events often appear only after cause of acute liver injury and hepatic failure worldwide,
the drug has been administered to a large global population often requiring liver transplantation. Marketed antibiotics –
with diverse medical histories. Toxicity-related drug failures amoxicillin-clavulanate, trimethoprim, and erythromycin
account for two-thirds of post-market withdrawals. 9 – also contribute to the list of hepatotoxic drugs.
For instance, aprotinin (Trasylol) was withdrawn NCEs, or withdrawn drugs such as nefazodone and
due to increased risk of death, Tegaserod (Zelnorm) due troglitazone, interfere with bile acid homeostasis, which
to heightened risk of heart attack and stroke, pergolide is vital for hepatocyte survival, by inhibiting the bile salt
mesylate (Permax) due to severe heart valve damage, export pump (BSEP), an ATP-binding cassette transporter
ximelagatran (Exanta), and pemoline (Cylert) due to their crucial for maintaining bilirubin and bile salt homeostasis.
hepatotoxicity, and rofecoxib (Vioxx) as it led to myocardial Inhibition of BSEP is a risk factor for cholestatic DILI,
infarction as a toxic effect. as it can cause accumulation of bile acids in hepatocytes,
thereby increasing liver toxicity. In addition, NCEs can
In the United States, drug toxicity is the leading cause
of acute hepatotoxicity, with over half of acute liver failures directly contribute to liver toxicity by altering the exposure
and clearance of drugs that are substrates for efflux
caused by idiosyncratic drug-induced liver injury (iDILI).
10
It is possible for iDILI to go unnoticed even in large phase transporters. Figure 2 illustrates the metabolic pathway of
III trials. troglitazone and its metabolites, which leads to cholestasis
and liver toxicity.
2.3. Drug-induced liver injury (DILI) An example of a toxicity-centric drug discovery strategy
DILI is among the most unpredictable adverse reactions involved identifying an active scaffold with single-digit
to xenobiotics in humans, causing hepatotoxicity, liver nM in vitro potency. In vivo studies were then conducted,

Volume 2 Issue 2 (2025) 31 doi: 10.36922/aih.4423