Swiss ADME Background For designing discovering or developing

Swiss. ADME Background. For designing, discovering or developing a therapeutically relevant molecule, potency and selectivity to the target protein is only one side of the problem. Indeed absorption, distribution, metabolism, and excretion (ADME) must be optimized for the molecule to reach its tissue/target in sufficient amount. To reduce off-target and unwanted effects, predictive cheminformatics is recognized as a valid alternative to experimental procedures 1. Objectives. The Swiss. ADME tool gives access through the web to a collection of models for predicting properties of small molecules and hence select the most promising to further study. CHEMICAL DESCRIPTION WATER SOLUBILITY Ponatinib is a small molecule (!) Ponatinib is poorly-tomoderately soluble èPotential problems for dose formulation. èSmall amount excreted by kidney. PHYSICOCHEMICAL DATA Ponatinib has an low TPSA (moderate apparent polarity). èwell absorbed by the GItract when taken orally. èprone to cross the Blood. Brain Barrier to enter the CNS. PHARMACOKINETICS Ponatinib is predicted as: èsubstrate of P-glycoprotein (efflux from the brain). èWell absorbed by GI-tract (suited for oral administration). OCTANOL/WATER PARTITION Ponatinib has a high log P (lipophilicity) èoxidation-prone by CYP 450. ètendency to be extensively bound to plasma proteins. èCan block h. ERG-channel. DRUGLIKENESS Ponatinib is considered as a druglike molecule by multiple filters (only size and refractivity are slightly above thresholds). èSuited for oral administration. step 2 (PK) step 3 (PD) step 1 (PD) MEDICINAL CHEMISTRY Ponatinib returned one alert (triple bound), which is a manageable problematic structural fragment. Ponatinib has a Synthetic Accessibility Score of 3. 42 (on a scale from 1 [easy to make] to 10 [very difficult to make]). èSuited for medicinal chemistry and biological screening activities. www. molecular-modeling. ch