Even though by extension it is often referred to as ligand efficiency, the concept was originally conceived to be strictly applicable to comparing the binding efficiencies of ligands for a single target. For a given target, comparing the le of all identified ligands can give a wide range, as many might not yet. Human salivary aldehyde dehydrogenase hsaldh protects us from the toxic effect of aldehydes. Structureactivity relationships, ligand efficiency, and.
The binding energymolecular size problem can be even more clearly highlighted with the help of a more quantitative metric characterizing ligand binding efficiency. One commonly used example is the ligand efficiency le, which is defined as. Validity of ligand efficiency metrics acs medicinal. Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. Ligand efficiency as a guide in fragment hit selection and optimization. G value dock score obtained in the docking experiment by number of nonhydrogen atoms. This evolution is a result of continuous efforts to hone potency and other desirable molecular properties.
Ligand efficiency and fragmentbased drug discovery, drug. Citral inhibits the dehydrogenase activity of hsaldh. Different classes of ligand efficiency metric are critically examined and the. Validity of ligand efficiency metrics europe pmc article. Conciliating binding efficiency and polypharmacology. Evidence of conformational selection driving the formation of ligand binding sites in proteinprotein interfaces. In addition, because it represents the balance of potency and molecular size, which is related to many admetox parameters as mentioned above, le can also be used to assess the quality of hit compounds. Glidescore number of heavy atoms ligand efficiency sa. The ligand efficiency parameters are described in glide docking output properties ligand efficiency. The idea of ligand efficiency binding energynonhydrogen atoms has recently emerged as a useful guide to optimize fragment and lead selection in the discovery process. Ligands can be compared effectively by a parameter ligand efficiency which can be calculated by dividing the. Binding thermodynamics and ligand efficiency hittolead.
Le is a key molecular property that is important in the assessment. Ligand efficiency le is defined as the binding energy per unit size, typically the binding free energy per nonhydrogen atom. Thus a focus on affinity leads to a bias towards a selection of bigger. The role of ligand efficiency measures in drug discovery. Advancing the activity cliff concept, part ii to a previously published commentary on the activity cliff concept, now reporting on i how this concept correlates with ligand efficiency measures of. We believe that it can be a very useful metric, but its simple and interpretable functional form kcalmolheavy atom means that it has deficiencies as well as strengths. Ligand efficiency an overview sciencedirect topics. Ligand efficiency le is, in essence, a good concept that is poorly served by a bad metric. Analysis of binding energy hot spots at protein surfaces can provide crucial insights into the prospects for successful application of fragmentbased drug discovery fbdd, and whether a fragment hit can be advanced into a highaffinity, druglike ligand. The utility of some ligand efficiency le metrics has recently been challenged in a viewpoint article in acs medicinal chemistry letters. However, in the context of fragmentbased drug design fbdd, these metrics often exhibit a strong emphasis toward the selection of highly efficient core fragments for potential optimization, which are not usually considered as parts of a larger molecule with a size. The ligand efficiency le indexes have long been used as decisionmaking criteria in drug discovery and development.
Scores for ligand efficiency have been proposed as guides for this process. Ligand efficiency le is the binding energy per ha hopkins et al. Using physicochemical measurements to influence better. For example, the first hiv1 protease inhibitor, saquinavir le 0. Available formats pdf please select a format to send. The aim of this work was to investigate the inhibitory effect and the mechanism of inhibition of citral on hsaldh.
Ligand efficiency metrics considered harmful springerlink. For fragment hit selection, le has become a widely accepted metric. Pdf lipophilic ligand efficiency as a useful metric in. This represents the first analysis of this type for the bromodomain family and can prove useful in the discovery of inhibitors, particularly for anticipating screening hit rates, identifying inhibitors that can be explored for lead hopping approaches, and selecting proteins for selectivity screening. Biophysical and computational fragmentbased approaches to. Lipophilic ligand efficiency as a useful metric in hit and lead optimization article pdf available january 2019 with 28 reads how we measure reads. Ligand lipophilicity efficiency physical properties.
In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. Ligand efficiency is a parameter recently introduced for selection of useful lead molecules in virtual screening of large datasets of compounds. Request pdf on jun 1, 2004, andrew l hopkins and others published ligand efficiency. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the. Pdf on jan 1, 2019, irannejad h and others published lipophilic ligand efficiency as a useful metric in hit and lead optimization find, read and cite all the research you need on researchgate. However, underlying all of these attempts are the actual compounds used to profile.
In particular, optimisation of lipophilic ligand efficiency shows that it is possible to. Citral possesses many biological and pharmacological properties. Discovery of two lead series with high ligand efficiency, journal of medicinal chemistry, 53 16. The ones marked may be different from the article in the profile. Ligand efficiency metrics quantify the molecular properties required to gain binding affinity for a drug target. More generalized concepts of ligand efficiency, related to efficiency per dalton and per unit of polar surface area. Biophysical screening in fragmentbased drug design. Also popular are the rule of three for lead compounds 19, and ligand efficiency metrics 20 21 22. The application of ligand efficiency le, a metric that relates the efficiency of potency per heavy atom in a ligand, is well established, in contrast to the use of lle which is just emerging 11. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Tuberculosis tb is an infectious, airborne disease caused by a pathogenic bacterium, mycobacterium tuberculosis. This efficiency metric approximates the effect of surface area. Xray crystallography protein structure is solved in presence of small organic molecules.
Pilot study on a small database of natural bioactive compounds. Ligand efficiency as a guide in fragment hit selection and. During the past decade, the physicochemical quality of molecules under investigation at all stages of the drug discovery process has come under. A useful metric for lead selection find, read and cite all the research. Le shows the expected behavior for a ratio of variables.
Ligand efficiency indices for effective drug discovery. This perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of proteinligand binding. This article also argued that earlier seminal work by lipinski has been misinterpreted and has led to an oversimplistic application of cutoffs for molecular properties such as mw fbdd. This article discusses the application of such metrics in the selection and. A useful metric for lead selection find, read and cite all the research you need on researchgate. The role of ligand efficiency metrics in drug discovery. Ligand efficiency and fragmentbased drug discovery ligand efficiency and fragmentbased drug discovery bembenek, scott d tounge, brett a reynolds, charles h. Structure guided lead generation toward nonchiral m. Thermodynamic profiling of proteinligand binding is increasingly used during lead optimization to find ligands that bind with high affinity. This cited by count includes citations to the following articles in scholar. Pdf lipophilic ligand efficiency as a useful metric in hit and lead. Drug discovery today autodocktools, the free gui for autodock.
The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. There are actually two ligand efficiencies in drug discovery and these can be seen as different manifestations of what might be. Lessons from hot spot analysis for fragmentbased drug. Advancing the activity cliff concept, part ii fresearch. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. It is a simple procedure where the initial slope of the curve describing the relationship between the concentration of complex at different ligand concentrations fig. The nature of ligand efficiency journal of cheminformatics full text. Limitations of ligand efficiency metrics and when to use them. Citral inhibition of human salivary aldehyde dehydrogenase.
Applying thermodynamic profiling in lead finding and. This bacterium primarily attacks the lungs and is often fatal if not treated promptly. Monitoring ligand efficiency metrics during hit and lead optimisation brings into. These strategies aim at the efficient optimization of fragments while maintaining their generally good. Modernprinciplesofsmallmoleculedrug discovery bymichaelrafferty,ph. Professor of medicinal informatics, university of dundee. Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. Fragmentbased drug discovery fbdd has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragmentsized mw pdf restore delete forever. The association between molecular size and risk of failure has promoted the use of binding efficiency as a prioritization metric in lead selection. Pdf on jan 1, 2019, irannejad h and others published lipophilic ligand efficiency as a useful metric in hit and lead optimization find, read and cite all the. Ligand efficiency is defined as the binding energy per unit size, typically the binding free energy per nonhydrogen atom.
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