title: 3D molecular descriptors important for clinical success.
abstract: The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.
authors.affiliation: Targacept, Inc., 200 East First Street, Suite 300, Winston-Salem, North Carolina 27101-4165, USA. dckombo777@mail.com
authors.forename: David C
authors.initials: DC
authors.lastname: Kombo
authors.forename: Kartik
authors.initials: K
authors.lastname: Tallapragada
authors.forename: Rachit
authors.initials: R
authors.lastname: Jain
authors.forename: Joseph
authors.initials: J
authors.lastname: Chewning
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Mazurov
authors.forename: Jason D
authors.initials: JD
authors.lastname: Speake
authors.forename: Terry A
authors.initials: TA
authors.lastname: Hauser
authors.forename: Steve
authors.initials: S
authors.lastname: Toler
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008024:Ligands; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D010600:Pharmacology; D011506:Proteins / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins