Statistical Analysis of the Effects of Common Chemical Substituents on Ligand Potency

Hajduk, Philip J.; Sauer, Daryl R.

doi:10.1021/jm070838y

Cited by 92 publications

(98 citation statements)

References 28 publications

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“…Importantly, owing to the symmetrical nature of the distributions, no significant enrichment in positive or negative outliers has been observed, implying that substantial increase and reduction in biological activity are equally probable. These results are consistent with earlier MMP-based analysis of substituent effects in medicinal chemistry [219], highlighting the fact that bioactivity change outliers spans through different target classes, molecular topologies, transformations, and IMHB atomic pairs [220].…”

Section: Intramolecular Hydrogen Bondssupporting

confidence: 90%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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The effect of weak intermolecular interactions on the binding affinity between ligand-protein complexes plays an important role in stabilizing a ligand at the interface of a protein structure. In this review article, we will explore the different ways of taking into account these interactions, mainly intramolecular hydrogen bonds, in docking calculations. Their possible limitations and their suitable application domains are highlighted. Inspection of the outliers of this study probed very stimulating, as it provides opportunities and inspiration to medicinal chemists, being a reminder of the impact that minimal chemical modifications can have on biological activities.

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Section: Intramolecular Hydrogen Bondssupporting

confidence: 90%

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

Yunta¹

2017

AJMO

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“…It shows that replacement of the 3,5-dimethoxyphenyl group in 1 by a 3,4-dimethoxyphenyl moiety (compound 2) significantly changes the FGFR1-bound A regiospecific effect of phenyl substitutions on ligand potency has previously been discussed by Hajduk et al In their statistical analysis of common chemical substitutions on ligand potency, they observed that the frequencies of achieving 10-fold losses in potency for dimethoxy substitutions are 2-fold higher for the 3,4-than for the 3,5-substitution pattern. 22 The FGFR1-bound conformation of the desmethoxy analog 3 (Figure 2d) is similar to the previous conformation of a close analog having a bromine substituent on the pyrimidine ring in complex with FGFR1 (PDB code: 4F65). 8 In contrast to the structures of FGFR1 in complex with the bromine substituted analog or 1, respectively, the observed electron density did not support the presence of a water molecule at the FGFR1−3 interface.…”

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confidence: 75%

FGFR1 Kinase Inhibitors: Close Regioisomers Adopt Divergent Binding Modes and Display Distinct Biophysical Signatures

Klein

Tucker

Holdgate

et al. 2013

ACS Med. Chem. Lett.

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The binding of a ligand to its target protein is often accompanied by conformational changes of both the protein and the ligand. This is of particular interest, since structural rearrangements of the macromolecular target and the ligand influence the free energy change upon complex formation. In this study, we use X-ray crystallography, isothermal titration calorimetry, and surface-plasmon resonance biosensor analysis to investigate the binding of pyrazolylaminopyrimidine inhibitors to FGFR1 tyrosine kinase, an important anticancer target. Our results highlight that structurally close analogs of this inhibitor series interact with FGFR1 with different binding modes, which are a consequence of conformational changes in both the protein and the ligand as well as the bound water network. Together with the collected kinetic and thermodynamic data, we use the protein−ligand crystal structure information to rationalize the observed inhibitory potencies on a molecular level. KEYWORDS: Receptor tyrosine kinase, induced fit, protein−ligand interactions, X-ray crystallography, isothermal titration calorimetry, surface plasmon resonance M embers of the fibroblast growth factor receptor (FGFR) family (FGFR1 to 4) serve as high affinity receptors for the fibroblast growth factors (FGFs) 1 and are key mediators of both developmental and disease-associated angiogenesis. 2 They are heavily implicated in the pathogenesis of tumor vascularization in a number of different tumor types, including breast, 3 pancreatic, 4 prostate, 5 and ovarian 6 carcinomas. Hence, they have been seen as attractive targets for the development of therapeutic agents 7 aimed at inhibiting tumor growth and metastasis through blockade of neovascularization. Recently, Norman et al. reported on the discovery of pyrazolylaminopyrimidines as potent FGFR1 inhibitors and their structure-based optimization that led to the identification of compound 1 (Figure 1). 8 In our continuing studies aimed at optimizing ligand-binding site interactions, the substitution pattern of the 3,5-dimethoxyphenyl group of 1 was varied. Interestingly, a tight structure−activity relationship was observed: moving one methoxy function from the 5-to the 4-position (compound 2) resulted in a drop of inhibitory potency/binding affinity of almost 2 orders of magnitude (Figure 1). Intrigued by this finding, we set about investigating the interaction between FGFR1 kinase and the selected pyrazolylaminopyrimidine inhibitors 1−3 using structural and biophysical analysis. Comparisons of the inhibitor binding modes as well as the accompanying kinetic and thermodynamic signatures provide detailed insights into the molecular determinants governing the different affinities of these structurally close inhibitors toward FGFR1 kinase.The crystal structure of FGFR1 in complex with 1 revealed the inhibitor to bind as expected with the pyrazolylaminopyr-

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“…It turns out that the distribution of affinity changes seen in actual compounds proposed by medicinal chemists is very nearly Gaussian and centered at an affinity change of zero. 77 Thus, a rather simple statistical analysis is possible. Screening a fixed number of compounds will result in finding an increasing number of highly potent compounds as the method's noise goes down (Fig.…”

Section: B Free Energy Calculations Could Guide Structure-based Designmentioning

confidence: 99%