Conformational analysis of peramivir reveals critical differences between free and enzyme-bound states

Richards, Michele R.; Brant, Michael G.; Boulanger, Martin J.; Cairo, Christopher W.; Wulff, Jeremy E.

doi:10.1039/c4md00168k

Cited by 7 publications

(8 citation statements)

References 37 publications

(40 reference statements)

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“…[45][46][47] Moreover, empirical force field-based methods, for instance based on the "General Amber Force Field" (GAFF 48,49 ) are not accurate enough to discriminate possibly subtle population shifts arising from free energy differences below 1 kcal mol -1 . This represents the typical so-called "chemical accuracy" which poses a systematic limit to force field 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1...…”

Section: Computational Studies Of Ligands' Conformation In Solutionmentioning

confidence: 99%

Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

et al. 2015

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Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.

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Section: Computational Studies Of Ligands' Conformation In Solutionmentioning

confidence: 99%

Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

et al. 2015

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“…Wulff et al have previously found that peramivir (5) has different conformational preferences in the solid-state, solution phase, and NA-bound complex. 23 To understand the binding modes in the active site of NA, we carried out the molecular docking experiments of 5 and the phosphonate congener 6a. Analysis of the molecular docking conformations of 5 in the NA active site (N1 subtype, PDB code 2HU4) 6 reveals that there is only little difference between modeling result and 5− NA cocrystal (Figure S1A,S1B in Supporting Information (SI)).…”

Section: ■ Introductionmentioning

confidence: 81%

Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors

et al. 2016

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Peramivir is a potent neuraminidase (NA) inhibitor for treatment of influenza infection by intravenous administration. By replacing the carboxylate group in peramivir with a phosphonate group, phosphono-peramivir (6a), the dehydration and deoxy derivatives (7a and 8a) as well as their corresponding monoalkyl esters are prepared from a pivotal intermediate epoxide 12. Among these phosphonate compounds, the dehydration derivative 7a that has a relatively rigid cyclopentene core structure exhibits the strongest inhibitory activity (IC50 = 0.3-4.1 nM) against several NAs of wild-type human and avian influenza viruses (H1N1, H3N2, H5N1, and H7N9), although the phosphonate congener 6a is unexpectedly less active than peramivir. The inferior binding affinity of 6a is attributable to the deviated orientations of its phosphonic acid and 3-pentyl groups in the NA active site as inferred from the NMR, X-ray diffraction, and molecular modeling analyses. Compound 7a is active to the oseltamivir-resistant H275Y strains of H1N1 and H5N1 viruses (IC50 = 73-86 nM). The phosphonate monoalkyl esters (6b, 6c, 7b, 7c, 8b, and 8c) are better anti-influenza agents (EC50 = 19-89 nM) than their corresponding phosphonic acids (EC50 = 50-343 nM) in protection of cells from the viral infection. The phosphonate monoalkyl esters are stable in buffer solutions (pH 2.0-7.4) and rabbit serum; furthermore, the alkyl group is possibly tuned to attain the desired pharmacokinetic properties.

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“…4 These can be further decorated to achieve, among other things, molecules like 8 that mimic the enzymebound state of the potent antiviral agent peramivir. 5,6…”

Section: Synform What Is Your Most Important Scientific Achievement Tmentioning

confidence: 99%

Synform Issue 2015/05

Zanda¹

2015

Synlett

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Conformational analysis of peramivir reveals critical differences between free and enzyme-bound states

Abstract: An analysis of the conformational distribution of peramivir, a potent anti-influenza compound, in solution and the solid state reveals a large conformational change required for enzyme binding.

Cited by 7 publications

References 37 publications

Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors

Synform Issue 2015/05

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