The influence of lead discovery strategies on the properties of drug candidates

Abstract

Despite the widespread acceptance of guidelines related to desirable physicochemical properties of potential small-molecule drugs, key properties - such as lipophilicity - of recently developed clinical candidates and advanced lead compounds have been shown to differ significantly from those of historical leads and drugs. By analysing the physicochemical properties of a large database of hits and corresponding leads identified in the past decade, we show that this undesirable phenomenon can be traced back to the nature of high-throughput screening hits and hit-to-lead optimization practices. Conceptual and organizational adjustments may be required to enable a smooth lead-evolution process that reduces the chance of high compound-related attrition in clinical trials.

The role of ligand efficiency metrics in drug discovery

“…The entropy-driven approach to improving affinity is probably a factor in the well-documented inflation of physicochemical properties in optimisation. 22,23,24,25 Although this picture is qualitative, thermodynamics-based optimizations have been the subject of increasing recent interest. 33,34 Isothermal titration calorimetry (ITC) allows the determination of H and TS, 35 and ITC data from more than 700 protein-ligand complexes, obtained from a literature survey covering both medicinal chemistry and natural-product derived ligands, has been analysed.…”

“…Firstly, the discovery of initial hit compounds with inflated physical properties has been linked to the rise of high-throughput screening (HTS). 23 Larger and more lipophilic compounds, potentially having greater binding affinity, are more likely to be detected in HTS assays, which are often based on a single affinity end point. Secondly, the tendency of HTS methods to identify large and lipophilic compounds is amplified by the observed tendency for the lead optimisation process to inflate physical properties.…”

Cell-based and virtual fragment screening for adrenergic α2C receptor agonists

“…To assist evaluation of binding efficiency, ligand efficiency (LE) and ligand-efficiency-dependent lipophilicity (LELP) were derived from K i values as described in the literature. 29,30 Table 1 demonstrates representative data for the validated hits. Numerous chemically diverse highly potent and efficient fragment hits were identified from this commercially available screening set.…”

A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds

“…Optimisation almost inevitably leads to increases in both molecular weight and lipophilicity, making it essential to control the properties of lead compounds. 6,7 The significant challenges associated with preparing diverse lead-like small molecules -i.e. molecules that would be good starting points for lead optimisation -have recently been articulated.…”