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. Ligand efficiency le is the binding energy per ha hopkins et al. The hydrogen bonding penalty can not only be used to filter unrealistic poses in docking, but also improve the. These strategies aim at the efficient optimization of fragments while maintaining their generally good. This evolution is a result of continuous efforts to hone potency and other desirable molecular properties. Binding thermodynamics and ligand efficiency hittolead.
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. Xray crystallography protein structure is solved in presence of small organic molecules. Ligand efficiency is a parameter recently introduced for selection of useful lead molecules in virtual screening of large datasets of compounds. For example, the first hiv1 protease inhibitor, saquinavir le 0. Lessons from hot spot analysis for fragmentbased drug.
Evidence of conformational selection driving the formation of ligand binding sites in proteinprotein interfaces. 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. 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. The role of ligand efficiency measures in drug discovery. 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. For fragment hit selection, le has become a widely accepted metric. The ligand efficiency le indexes have long been used as decisionmaking criteria in drug discovery and development. Discovery of two lead series with high ligand efficiency, journal of medicinal chemistry, 53 16. Glidescore number of heavy atoms ligand efficiency sa. The utility of some ligand efficiency le metrics has recently been challenged in a viewpoint article in acs medicinal chemistry letters.
G value dock score obtained in the docking experiment by number of nonhydrogen atoms. Ligands can be compared effectively by a parameter ligand efficiency which can be calculated by dividing the. The association between molecular size and risk of failure has promoted the use of binding efficiency as a prioritization metric in lead selection. Structure guided lead generation toward nonchiral m. During the past decade, the physicochemical quality of molecules under investigation at all stages of the drug discovery process has come under. Ligand efficiency le is defined as the binding energy per unit size, typically the binding free energy per nonhydrogen atom. This efficiency metric approximates the effect of surface area. Request pdf on jun 1, 2004, andrew l hopkins and others published ligand efficiency. One commonly used example is the ligand efficiency le, which is defined as. 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. In this work, the change of hydrogen bonding energy in the binding process, namely hydrogen bonding penalty, is evaluated with a new method. Available formats pdf please select a format to send. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads.
Lipophilic ligand efficiency as a useful metric in hit and lead optimization article pdf available january 2019 with 28 reads how we measure reads. Tuberculosis tb is an infectious, airborne disease caused by a pathogenic bacterium, mycobacterium tuberculosis. Citral inhibits the dehydrogenase activity of hsaldh. 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. 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. Ligand efficiency as a guide in fragment hit selection and. Drug discovery today autodocktools, the free gui for autodock. Limitations of ligand efficiency metrics and when to use them. For a given target, comparing the le of all identified ligands can give a wide range, as many might not yet.
More generalized concepts of ligand efficiency, related to efficiency per dalton and per unit of polar surface area. Modernprinciplesofsmallmoleculedrug discovery bymichaelrafferty,ph. Ligand binding involves breakage of hydrogen bonds with water molecules and formation of new hydrogen bonds between protein and ligand. Validity of ligand efficiency metrics europe pmc article. Advancing the activity cliff concept, part ii fresearch. This bacterium primarily attacks the lungs and is often fatal if not treated promptly. Professor of medicinal informatics, university of dundee. Using physicochemical measurements to influence better. Biophysical screening in fragmentbased drug design. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Ligand efficiency metrics considered harmful springerlink. 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. 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.
The ligand efficiency parameters are described in glide docking output properties ligand efficiency. Ligand efficiency and fragmentbased drug discovery, drug. Citral possesses many biological and pharmacological properties. The ones marked may be different from the article in the profile. Monitoring ligand efficiency metrics during hit and lead optimisation brings into. This perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of proteinligand binding. 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. This article discusses the application of such metrics in the selection and. The role of ligand efficiency metrics in drug discovery. This cited by count includes citations to the following articles in scholar.
Ligand efficiency an overview sciencedirect topics. Le is a key molecular property that is important in the assessment. The key factor is the strength of the top ranking hot spot, and how well a given fragment complements it. 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. Pdf lipophilic ligand efficiency as a useful metric in. Structureactivity relationships, ligand efficiency, and. 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. Thus a focus on affinity leads to a bias towards a selection of bigger. Ligand efficiency le is, in essence, a good concept that is poorly served by a bad metric.
The aim of this work was to investigate the inhibitory effect and the mechanism of inhibition of citral on hsaldh. Pdf lipophilic ligand efficiency as a useful metric in hit and lead. Le shows the expected behavior for a ratio of variables. Citral inhibition of human salivary aldehyde dehydrogenase. A useful metric for lead selection find, read and cite all the research. A useful metric for lead selection find, read and cite all the research you need on researchgate. 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. Different classes of ligand efficiency metric are critically examined and the. 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.
There are actually two ligand efficiencies in drug discovery and these can be seen as different manifestations of what might be. Applying thermodynamic profiling in lead finding and. Conciliating binding efficiency and polypharmacology. Also popular are the rule of three for lead compounds 19, and ligand efficiency metrics 20 21 22. Ligand efficiency is defined as the binding energy per unit size, typically the binding free energy per nonhydrogen atom.
Biophysical and computational fragmentbased approaches to. 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 metrics quantify the molecular properties required to gain binding affinity for a drug target. Thermodynamic profiling of proteinligand binding is increasingly used during lead optimization to find ligands that bind with high affinity. The nature of ligand efficiency journal of cheminformatics full text. Pilot study on a small database of natural bioactive compounds. Validity of ligand efficiency metrics acs medicinal. The binding energymolecular size problem can be even more clearly highlighted with the help of a more quantitative metric characterizing ligand binding efficiency. Human salivary aldehyde dehydrogenase hsaldh protects us from the toxic effect of aldehydes. Ligand efficiency as a guide in fragment hit selection and optimization. Scores for ligand efficiency have been proposed as guides for this process. Ligand efficiency indices for effective drug discovery.
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