10.1021/ci300445e.s005 David C. Kombo David C. Kombo Kartik Tallapragada Kartik Tallapragada Rachit Jain Rachit Jain Joseph Chewning Joseph Chewning Anatoly A. Mazurov Anatoly A. Mazurov Jason D. Speake Jason D. Speake Terry A. Hauser Terry A. Hauser Steve Toler Steve Toler 3D Molecular Descriptors Important for Clinical Success American Chemical Society 2013 ligand Fsp 3 criteria Clinical SuccessThe pharmacokinetic MDDR phase 1 stages vs compounds Sp 3 carbon atoms Fsp 3 MDL Drug Data Report descriptor physicochemical properties 3 D Molecular Descriptors stereo centers 2013-02-25 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/3D_Molecular_Descriptors_Important_for_Clinical_Success/2440726 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these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD.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 We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria.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.