Ligand efficiency indices for effective drug discovery

Abstract

Successful drug discovery requires the optimization of a large number of variables ranging from strictly physicochemical parameters such as molecular weight to more complex parameters related to toxicity and bioavailability. Presently, structure-based methodologies influence many aspects of the drug discovery process from lead discovery to the final preclinical characterization. However, critical biological issues along the path to the market have diminished the impact and power of this methodology. The physicochemical properties of the novel chemical entities designed and guided by structural methods have become the subject of intense scrutiny from lead discovery to drug candidate. The idea of ligand efficiency (binding energy/non-hydrogen atoms) has recently emerged as a useful guide to optimize fragment and lead selection in the discovery process. More generalized concepts of ligand efficiency, related to efficiency per dalton and per unit of polar surface area, have also been introduced and will be discussed in the broader context. Preliminary results and trends obtained using ligand efficiencies as guides are reviewed and their future application to guide drug discovery will be discussed, as well as their integration into the structure-based drug design methods to make them more effective and numerically robust.

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…This conclusion is supported by comparative evaluation of HEDICIN and HECIN ligand efficiencies, as follows. Enzyme inhibitor candidates can be profiled regarding their ligand efficiencies by use of simple techniques, originally developed to provide a fast and simple way of assessing the quality of hits in high-throughput screening efforts [34]. As ligand efficiency is expectedly lower for smaller compounds, given the fewer contact points with the target enzyme, ligand size is a key parameter in calculating ligand quality [35].…”

AtlasCBS: a web server to map and explore chemico-biological space

“…1b, 2b and 3. Therefore, in the near future, it is theoretically possible to envisage an automatic procedure that optimizes ligand efficiencies by replacing some molecular fragments and evaluates the LEIs of the new candidates in an iterative fashion, until the best possible ligand(s) is(are) found [15]. It is precisely here that the future power of this methodology and graphical representation should be apparent: as a graphical and numerical guide in the search for better drug candidates.…”

“…3) illustrate a very important use of the efficiency planes presented by the AtlasCBS tool that could impact the future of drug discovery. Namely, that compounds with maximal efficiencies in size and polarity are often the best suited preclinical candidates for further development and often correspond to the successful marketed drug, as supported by other retrospective studies [13][14][15]. This notion can be extensively explored using the server and the available data as represented in various efficiency planes.…”

“…Using as a guide the suggestion that compounds with maximal efficiencies are likely to be good candidates for further development, we propose that the above strategy and the use of the AtlasCBS server would be useful to the drugdiscovery community. This could set the basis for a more rigorous, numerically and efficiency-based, drug discovery paradigm [15]. Fig.…”

Potential of agricultural fungicides for antifungal drug discovery

“…Other simplified rule-based drug-likeness and/or lead-likeness definitions were summarized by, for example, AbadZapatero or Walters. [37,38] Rules based on the Lipinski's approach aimed at improvement of oral bioavailability and redistribution of agrochemicals were adopted quickly, see Table 2. Selected agricultural fungicides (including mode of action and FRAC target site code) potentially interesting for drug design.…”