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Absorption, distribution, metabolism, and elimination govern drug concentration in tissues -- potency is irrelevant if ADME prevents the drug from ever arriving.

Anticipated human dose (AHD) converts predicted human pharmacokinetics and a PK/PD target into a concrete dose and dosing frequency, serving as the final candidate selection gate.

The biopharmaceutics classification system (BCS) organizes oral compounds into four classes by solubility and intestinal permeability, predicting where formulation effort is needed.

Half-life is determined by the ratio of volume of distribution to clearance; together these parameters predict how long a drug maintains therapeutic exposure.

Drug programs fail mostly because alternate biological pathways bypass the target, not because the chemistry fails.

A drug's pKa and the GI tract's pH gradient together determine whether it is ionized or neutral at each location, which in turn controls where dissolution and absorption occur.

A drug program starts by defining what existing treatments lack, not by identifying promising molecules.

A formulation success that finally enables adequate drug exposure can immediately reveal that the compound isn't safe -- producing an early program-ending answer that costs far less than a late one.

Imatinib (Gleevec) moved from weak BCR-ABL binding to an orally bioavailable CML drug through sequential modifications: improve binding, fix selectivity, then enable oral absorption.

Blocking the hERG potassium channel delays cardiac repolarization, prolonging the QT interval and risking torsades de pointes -- a potentially fatal arrhythmia.

Potency in a binding assay isn't enough -- hits advance only when selectivity, physicochemical properties, PK viability, and safety margins also pass.

High-throughput screening tests up to 100,000 compounds per day with robots and selects the top 0.1% above a statistical threshold as confirmed hits.

Solubility, permeability, and metabolic stability assays filter compounds for PK viability before expensive animal studies, using IVIVC to validate the predictions.

Lipophilic efficiency (LiPE = pIC₅₀ - logD) normalizes potency by lipophilicity, exposing which compounds achieve binding efficiently rather than through brute hydrophobicity.

More lipophilic compounds bind targets more potently but also show lower solubility, faster metabolism, higher toxicity risk, and broader nonspecific protein binding.

A pharmacophore is the minimal set of interaction types (hydrogen bond donors, acceptors, hydrophobic groups) a compound needs to bind its target -- abstracting SAR into a design blueprint.

Phenotypic programs work to identify the target they hit; TBDD programs gather phenotypic validation -- both approaches evolve toward each other.

Preclinical toxicology runs in parallel with clinical trials, with study types and durations matched to the scope of human exposure at each phase.

Safety pharmacology tests acute functional effects on cardiovascular, CNS, and respiratory systems -- distinct from the slow-accumulating damage that general toxicology monitors.

Reacting a drug molecule with acids or bases creates salt forms with different solubility, dissolution rate, and crystal structure -- same active pharmacology, different delivery behavior.

Structure-activity relationships emerge from testing systematic analogs of a hit, converting a single active molecule into a gradient that guides optimization.

TBDD is fast and iterative but bets that modulating one target will actually change the disease, a bet biology often defeats.

Therapeutic index (TI) compares the dose that causes harm to the dose that produces benefit; it's the quantitative expression of a drug's risk-benefit margin.

Z-factor (0 to 1) measures the separation between positive and negative controls; it's a go/no-go gate before screening a million compounds.