3D Molecular Descriptors
Important for Clinical Success
David C. Kombo
Kartik Tallapragada
Rachit Jain
Joseph Chewning
Anatoly
A. Mazurov
Jason D. Speake
Terry A. Hauser
Steve Toler
10.1021/ci300445e.s004
https://acs.figshare.com/articles/dataset/3D_Molecular_Descriptors_Important_for_Clinical_Success/2440723
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vs compounds withdrawn from the market better than do Fsp3 and LogD.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withdrawn and discontinued compounds fail to meet the same criteria.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.
2013-02-25 00:00:00
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