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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The advantages of screening low-molecular-weight fragment-based libraries compared to traditional higher-molecular-weight chemical libraries include the potential identification of hydrophilic hits in which hydrogen bonding is more likely to contribute to affinity (i.e., enthalpically driven binding). After this, binding affinity can be further enhanced by adding hydrophobic groups (i.e., to promote entropically driven binding). Furthermore, starting with a hydrophilic ligand increases the chances that the final optimized ligand will not be too hydrophobic overall (i.e., log P < 5). Furthermore, a higher ligand efficiency means that the final optimized ligand will most likely have a relatively low molecular weight (i.e., <500). Since, in theory, two to three fragments can be combined to form an optimized ligand, proponents of this methodology claim that screening a fragment library of “n” compounds is equivalent to screening 2n–3n compounds in a traditional library. Also, fragments are less likely to contain sterically blocking groups that interfere with an otherwise favorable ligand–protein interaction.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Over the past two decades, fragment-based approaches have gained traction as alternative and complementary hit finding mechanisms to target-based and phenotypic high-throughput screening (HTS) (Erlanson et al. 2016). By contrast with HTS, which involves screening of a large library (typically tens to hundreds of thousands) of drug-like compounds in a high-throughput assay, a classical fragment-based approach begins with the screening of a small library (typically 1000–5000) of fragments (chemicals of low molecular weight and complexity), primarily using biophysical techniques. The goal of a fragment screen is to identify chemicals that bind a target efficiently. As a consequence of their low molecular weight and size, fragments invariably bind with low affinity, and therefore metrics are used that attempt to normalize affinity for properties such as molecular weight. The most popular metric is ligand efficiency (LE), in which the free energy of binding of a compound is divided by the number of non-hydrogen atoms (NHA) that compound has (reported in units of kcal.mol–1.NHA–1) (Hopkins et al. 2004). Provided sufficient structural information is available, weakly, but efficiently binding fragment hits can be elaborated iteratively into higher affinity binders with drug-like properties. Fragments are commonly elaborated by growing (the iterative addition of moieties designed to pick up interactions in neighboring regions of a binding site), merging (the amalgamation of fragments binding in overlapping binding sites into a single molecule), or linking (the fusion of two fragments binding in adjacent regions of a binding site through a chemical linker). For a review of fragment screening approaches and discussion of fragment elaboration strategies, the reader is referred to Scott et al. (2012).
Inhibition of acetylcholinesterase and butyrylcholinesterase with uracil derivatives: kinetic and computational studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Huseyin Cavdar, Murat Senturk, Murat Guney, Serdar Durdagi, Gulru Kayik, Claudiu T. Supuran, Deniz Ekinci
Both GOLD and Glide docking results fit to experimental findings (Table 1). Scores of top docking poses of compound 4 show higher scores compared to other molecules. In GOLD, higher GoldScore Fitness scoring values represent tighter binding interactions. Results also show ligand efficiency scores (LIE) of studied molecules. In order to escape the affinity-biased selection and optimisation towards larger ligands, Hopkins et al.33recommended to assess binding affinity in relation to number of heavy atoms in a molecule and introduced the term ligand efficiency (the average affinity contribution per atom is considered) instead of considering the affinity of the whole compound. This provides a way to compare the affinity of molecules corrected for their size. In our case, we used Glide/XP scores for the calculation of ligand efficiency scores (ligand efficiency: GlideScore/number of heavy atoms). Results show that compound 3 has top-scored LIE values both in AChE and BuChE.
Discovery of new butyrylcholinesterase inhibitors via structure-based virtual screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Noor Atatreh, Sara Al Rawashdah, Shaikha S. Al Neyadi, Sawsan M. Abuhamdah, Mohammad A. Ghattas
With regard to the in silico data, docking results for the six active hits are shown in Table 2. All active compounds exhibited low binding energies ranging from (−10.3 to −16.3 kcal/mol). These scores seem to be even more interesting if they got related to the size of the molecule since these hits scored ligand efficiency scores of around −0.5 kcal/mol. Ligand efficiency scores are calculated by dividing the docking score over the molecule weight of the compound and it indicates for suitability of the ligand to act as lead compound. Hence, these compounds look to have interesting binding energies with relatively small size when compared with the co-crystallised ligand.
Ligand efficiency indices for effective drug discovery: a unifying vector formulation
Published in Expert Opinion on Drug Discovery, 2021
This brief detour is the right place to discuss two issues that are related to the development of the field of ligand efficiency indices: (i) the controversy about the inadequacy of the equations defining some of them [12] and (ii) the ‘size dependence’ of the ligand efficiency variables and the various attempts to derive ‘size-independent’ relationships related to various numerators [13–15].