Abstract:
: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. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different classes of ligand efficiency metric are critically examined and the study concludes with suggestions for alternative ways to account for physicochemical properties when prioritizing and optimizing leads.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Kenny PW,Leitão A,Montanari CAdoi
10.1007/s10822-014-9757-8subject
Has Abstractpub_date
2014-07-01 00:00:00pages
699-710issue
7eissn
0920-654Xissn
1573-4951journal_volume
28pub_type
杂志文章abstract::The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand ...
journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-019-00249-1
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abstract::The bacterial ribosome is a major target of naturally occurring thiopeptides antibiotics. Studying thiopeptide (e.g. thiostrepton) binding to the GAR's 23S·L11 ribosomal subunit using docking methods is challenging. Regarding the target, the binding site is composed of a flexible protein-RNA nonbonded interface whose ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9797-0
更新日期:2014-12-01 00:00:00
abstract::A linear quantitative-structure activity relationship model is developed in this work using Multiple Linear Regression Analysis as applied to a series of 51 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides derivatives with CCR5 binding affinity. For the selection of the best variables the Elimination Selection-Step...
journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-006-9038-2
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abstract::Electrostatic potential complementarity between ligands and their receptor sites is evaluated by the superposition of the electrostatic potential, generated by the receptor, onto the ligand potential over the ligand van der Waals surface. We would like to examine which structural factors generate this pattern of super...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00123665
更新日期:1994-10-01 00:00:00
abstract::G Protein-Coupled Receptors (GPCRs) constitute a superfamily of receptors that forms an important therapeutic target. The number of known GPCR sequences and related information increases rapidly. For these reasons, we are developing the Viseur program to integrate the available information related to GPCRs. The Viseur...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008170432484
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abstract::Molecular structures and functions of the majority of proteins across different species are yet to be identified. Much needed functional annotation of these gene products often benefits from the knowledge of protein-ligand interactions. Towards this goal, we developed eFindSite, an improved version of FINDSITE, design...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-013-9663-5
更新日期:2013-06-01 00:00:00
abstract::We apply an atomistic model of passive membrane permeability to a series of weakly basic drugs. The computational model uses conformational sampling in combination with an all-atom force field and implicit solvent model to estimate relative passive membrane permeabilities. The model does not require the use of trainin...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-007-9141-z
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abstract::Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimizati...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1013104713913
更新日期:2001-09-01 00:00:00
abstract::Macroscopic pKa values were calculated for all compounds in the SAMPL6 blind prediction challenge, based on quantum chemical calculations with a continuum solvation model and a linear correction derived from a small training set. Microscopic pKa values were derived from the gas-phase free energy difference between pro...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-018-0138-6
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000030037.67742.cb
更新日期:2004-02-01 00:00:00
abstract::Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00126666
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abstract::The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensio...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00124460
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abstract::The pharmacophoric concept plays an important role in ligand-based drug design methods to describe the similarity and diversity of molecules, and could also be exploited as a molecular representation scheme. A three-point pharmacophore method was used as a molecular representation perception. This procedure was implem...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-007-9110-6
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-010-9388-7
更新日期:2010-12-01 00:00:00
abstract::In this work, we present a case study to explore the challenges associated with finding novel molecules for a receptor that has been studied in depth and has a wealth of chemical information available. Specifically, we apply a previously described protocol that incorporates explicit water molecules in the ligand bindi...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-9963-7
更新日期:2016-10-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-008-9182-y
更新日期:2008-09-01 00:00:00
abstract::Computational prediction of the effects of residue changes on peptide-protein binding affinities, followed by experimental testing of the top predicted binders, is an efficient strategy for the rational structure-based design of peptide inhibitors. In this study we apply this approach to the discovery of competitive a...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-012-9574-x
更新日期:2012-07-01 00:00:00
abstract::We have developed PLASS (Protein-Ligand Affinity Statistical Score), a pair-wise potential of mean-force for rapid estimation of the binding affinity of a ligand molecule to a protein active site. This scoring function is derived from the frequency of occurrence of atom-type pairs in crystallographic complexes taken f...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000046819.20241.16
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abstract::An analysis of five different datasets of inhibitors of serotonin uptake has yielded quantitative structure/activity relationships (QSARs) which delineate the role of steric and hydrophobic properties essential for inhibition by phenylethylamine-type analogues. ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00125664
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/BF00124319
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-009-9315-y
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1021242018286
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abstract::The Ligand Design (LUDI) approach has been used in order to design leucine aminopeptidase inhibitors, predict their activity and analyze their interactions with the enzyme. The investigation was based on the crystal structure of bovine lens leucine aminopeptidase (LAP) complexed with its inhibitor--the phosphonic acid...
journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-017-0053-2
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abstract::Two new continuum solvation models have been presented recently, and in this paper they are explained and reviewed in detail with further examples. Solvation Model 2 (AM1-SM2) is based on the Austin Model 1 and Solvation Model 3 (PM3-SM3) on the Parameterized Model 3 semiempirical Hamiltonian. In addition to the incor...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00126219
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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abstract::The complex of adenylate kinase with its transition-state inhibitor has been studied by molecular dynamics simulations in water and in vacuum environments with the GROMOS force field over a period of 300 ps. The adenylate kinase, a member of the nucleotide-binding protein family, was exemplarily chosen for the inspect...
journal_title:Journal of computer-aided molecular design
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