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these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD.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 We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria.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.

One‐Pot Enantioselective Synthesis of 1,4‐Naphthoquinone‐Derived Polycycles through Oxidative Dearomatization and Aminocatalysis

“…[c] Diastereomeric ratios were determined by 1 Having identified optimal reaction conditions ( Table 1, Entry 8), we set out to explore the substrate scope of this chemistry with respect to other dienal substrates (Scheme 2).…”

“…These structures are exceptionally interesting because an increase in saturation, as measured by the fraction of sp 3 carbon atoms, and a high number of asymmetric centers in the molecular structures, tend to correlate with clinical success. [1] In terms of making natural products, synthetic strategies based on the formation of nonaromatic chiral polycycles from simple building blocks has been harnessed by several research groups. [2] In particular, the marriage of oxidative dearomatization and asymmetric catalysis in a single vessel has emerged as an attractive strategy to increase molecular complexity from simple and readily-introduced functionalities.…”

Comparative Study on the Use of Docking and Bayesian Categorization To Predict Ligand Binding to Nicotinic Acetylcholine Receptors (nAChRs) Subtypes

“…26,30 Numerous studies on virtual screening targeting nAChRs have also been reported by others in recent years. 31−41 Most of these studies have used molecular docking approach.…”

A step-economical multicomponent synthesis of 3D-shaped aza-diketopiperazines and their drug-like chemical space analysis

“…5 In addition, shape-based 3D descriptors such as the radius of gyration (ROG) and shadow indices (Shadow Xlength, SXL) explicitly describe the compactness and flatness of a compound, and therefore represent an efficient way to evaluate the propensity of a compound to advance from clinical trials to the market. 15 Although predictions based solely on physicochemical properties should be taken with care, drug candidates successfully advancing to clinical trials tend to share the following properties: SXL ≤ 16.09; ROG < 4.11; F sp 3 ≥ 0.42. Additionally, the chance of a preclinical candidate passing through the different clinical trial stages was also evaluated by the quantitative estimate of the drug-likeness (QED) descriptor.…”