IN SILICO ENDPOINTS

Mutagenicity (Ames test)

The Ames test is an in vitro method used to evaluate the mutagenic potential of chemical compounds. The test is based on the principle of reverse mutations in several strains of bacteria (Salmonella typhimurium and Escherichia coli) induced by the tested compound. It is a regulatory genotoxicity test conducted in the early stage of non-clinical safety studies.

Genotoxicity: in vitro micronucleus test

The in vitro micronucleus test is a genotoxicity test for the detection of micronuclei in the cytoplasm of cells. Micronuclei may contain chromosome fragments produced from DNA breakage (clastogens) or whole chromosomes produced by disruption of the mitotic apparatus (aneugens).

Genotoxicity: in vivo micronucleus test (mouse)

The in vivo micronucleus test is a genetic toxicology method used to evaluate the capability of chemical compounds to provoke the formation of micronuclei, which are indicative of both clastogenic (lagging chromosome fragments) and aneugenic (whole chromosome) effects of the tested substances. The training dataset comprises results from in vivo micronucleus assays conducted on mouse bone marrow and/or blood erythrocytes.

hERG cardiotoxicity

hERG (human Ether-a-go-go Related Gene) inhibition refers to the ability of a drug or chemical compound to block the hERG potassium ion channel, which plays a critical role in cardiac repolarization. Inhibition of the hERG channel can lead to prolongation of the QT interval in the electrocardiogram which can increase the risk of a potentially life-threatening cardiac arrhythmia. The models were developed using training data from in vitro whole-cell patch clamp electrophysiology assays and binding assays, such as radio-ligand replacement assay.

Carcinogenicity

The two-year rodent bioassay is considered the benchmark method to assess carcinogenic potential of a chemical and provides information on the possible health hazards associated with repeated exposure of the used species over a period lasting up to the entire lifespan. Separate models are constructed for both sexes of rats and mice, as well as a general model that includes both species.

Hepatotoxicity (DILI)

Drug-induced liver injury (DILI) represents one of the major drug-induced adverse events leading to life-threatening conditions such as acute liver failure. It is also the second most common source of clinical attrition, precautionary warnings, and post-market withdrawal of drugs. The training dataset includes human hepatotoxicity data of pharmaceuticals. Data is annotated based on FDA drug labels after verification for causality. DILI descriptions covered serum enzyme elevations, occurrence of jaundice, hospitalizations, or other severe symptoms such as hepatic failure and/ or liver transplant.

Drug induced nephrotoxicity (DIN)

Drug-induced nephrotoxicity (DIN) refers to renal damage resulting either directly or indirectly from pharmaceutical substances. Nephrotoxicity presents a major clinical challenge as it is usually identified late in the drug development process, contributing to 2% of drug failures in pre-clinical studies and 19% in phase.

Acute oral toxicity (AOT)

Acute oral toxicity (AOT) refers to the adverse effects or harm caused by the ingestion of a substance, such as a chemical, drug, or toxic compound, within a relatively short period of time. acute toxicity is generally evaluated using AOT tests that assess acute toxic reactions and the lethal dose 50 (LD50) after a single oral administration to rodents. The LD50 is defined as the dose of the test substance that can kill 50% of animals within 24 h of exposure. The training dataset includes LD50 data collected from rat acute oral systemic toxicity tests and divided into two categories as follows: toxic (LD50 <= 2000mg/kg) and nontoxic (LD50 > 2000mg/kg), according to the recommendations of Consumer Product Safety Commission (CPSC) and U.S. Department of Defense (DoD) agencies.

Acetylcholinesterase (AChE) inhibition

Acetylcholinesterase (AChE) is an enzyme responsible for breaking down the neurotransmitter acetylcholine. Inhibition of AChE can lead to an accumulation of acetylcholine, disrupting normal neurotransmission processes. This is often seen in the context of exposure to neurotoxic substances, such as certain pesticides, which can lead to AChE inhibition and subsequent neurotoxic effects.

Physicochemical Properties

Aqueous solubility (logS)

Aqueous solubility is a physicochemical property that represents the amount of a substance (solute) that can be dissolved in water at a specific temperature. Predicted results of the models are valid for a temperature at 25 C. The reported value is logS (in logarithmic units), which is the 10-based logarithm of the solubility measured in mol/L.

Human plasma protein binding (PPB)

Plasma protein binding refers to the reversible attachment of drugs to proteins in the bloodstream, primarily albumin and alpha-1 acid glycoprotein. This process can affect a drug's absorption, distribution, metabolism and excretion (ADME) with consequences in clinical effectiveness, as only the unbound fraction is pharmacologically active. The training dataset comprised of human PPB records.

Blood-brain barrier (BBB) permeability

The passage across the blood-brain barrier (BBB) is one of the crucial factors governing the pharmacokinetic behavior of drugs and bioactive substances in both humans and animals. Neuroactive drugs must successfully breach the BBB to exert their therapeutic effects. Conversely, periphery acting drugs should ideally refrain from crossing the BBB to mitigate the potential for unwanted psychotropic side effects. The most common numeric value describing permeability across BBB is the logBB, which is defined as logarithmic ratio between the concentration of a compound in brain and blood.

Human intestinal absorption

Human intestinal absorption refers to the process through which orally administered substances, such as pharmaceutics, nutrients and various compounds are absorbed from the gastrointestinal system into the bloodstream of the human body. It represents one of the key processes determining the bioavailability of drugs and other compounds.

Caco-2 permeability

Caco-2 permeability refers to a commonly used assay that measures the ability of a substance to pass through a layer Caco-2 cells derived from human colon epithelial cancer cells. Studying the permeability of compounds across a Caco-2 cell monolayer is an established in vitro reference technique to screen for oral dosing and predict intestinal absorption of drugs and other xenobiotics.

Inhibition of human Cytochrome P450 enzymes

Cytochrome P450 enzymes (CYP450) play a critical role in metabolizing drugs and detoxifying poisonous compounds. Approximately 90% of drugs undergo metabolism through five main isoforms (CYP3A4, 2C9, 2D6, 2C19, 1A2). Alterations in CYP activity can impact drug activity and clearance. Assessing drug inhibitory potential against CYP450 is crucial for the study of drug-drug interactions and toxicities.