title: In silico physicochemical parameter predictions.
abstract: Drug discovery is a complex process with the aim of discovering efficacious molecules where their potency and selectivity are balanced against ADMET properties to set the appropriate dose and dosing interval. The link between physicochemical properties and molecular structure are well established. The subsequent connections between physicochemical properties and a drug's biological behavior provide an indirect link back to structure, facilitating the prediction of a biological property as a consequence of a particular molecular manipulation. Due to this understanding, during early drug discovery in vitro physicochemical property assays are commonly performed to eliminate compounds with properties commensurate with high attrition risks. However, the goal is to accurately predict physicochemical properties to prevent the synthesis of high risk compounds and hence minimize wasted drug discovery efforts. This paper will review the relevance to ADMET behaviors of key physicochemical properties, such as ionization, aqueous solubility, hydrogen bonding strength and hydrophobicity, and the in silico methodology for predicting them.
authors.affiliation: AstraZeneca R&D Alderley Park, DMPK, Mereside, Macclesfield, Cheshire, SK10 4TF, United Kingdom. mark.wenlock@astrazeneca.com
authors.forename: Mark C
authors.initials: MC
authors.lastname: Wenlock
authors.forename: Patrick
authors.initials: P
authors.lastname: Barton
mesh_terms: D000465:Algorithms; D019817:Benzoic Acid / Q000737:chemistry; D002228:Carbenicillin / Q000737:chemistry; D002627:Chemistry, Physical / Q000379:methods; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D012459:Salicylates / Q000737:chemistry; D012995:Solubility
chemical_list: D012459:Salicylates; D019817:Benzoic Acid; D002228:Carbenicillin; C014182:salicylsalicylic acid