Exploring Inhibitor Binding at the S′ Subsites of Cathepsin L

Chowdhury, Subrata; Joseph, Lissa; Kumar, Srinivasan Dinesh; Shenoy, Rajesh T.; Bhat, Sathesh; Ziomek, Edmund; Ménard, Robert; Sivaraman, J.; Purisima, Enrico O.

doi:10.1021/jm701190v

Cited by 29 publications

(34 citation statements)

References 45 publications

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“…Figure 2a shows the simulated annealing F o -F c omit map for inhibitor 4. 7,8 The crystal structures of 4, 9, and 14 are reported in the current paper.…”

Section: Resultsmentioning

confidence: 98%

“…Figure S1a). 7,8 The Arg residue of the inhibitor is located in S1 with its side chain solvent-exposed and its backbone carbonyl making a hydrogen bond with the NH group of Gly68. In the S2 subsite, the inhibitor Tyr side chain has nonpolar interactions with Leu69, Met70, and Ala135 and its amide NH forms a hydrogen bond with the Gly68 carbonyl.…”

Section: Resultsmentioning

confidence: 99%

“…The 4-biphenylacetyl group is found to be in a conformation different from inhibitors 4 and 9 a n di si nav e r y extended conformation reaching toward putative S3 0 subsite ( Figure 1c) discussed previously. 7 The biphenyl group stacks against Trp189 and interacts with Gln21 on the other face of the rings. At the farthest tip of the biphenyl group there is some contact with the Cβ of Trp193.…”

Section: Resultsmentioning

confidence: 99%

“…7,8 These inhibitors showed nanomolar potency and high selectivity for cathepsin-L. The first crystal structure of such an inhibitor (PDB code 1MHW) confirmed the reverse-binding noncovalent nature of inhibition.…”

Section: Introductionmentioning

confidence: 87%

“…Binding affinities were taken from published data. 7,8 Cocrystallization and Data Collection. Inhibitor 4.…”

Section: Methodsmentioning

confidence: 99%

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A Combined Crystallographic and Molecular Dynamics Study of Cathepsin L Retrobinding Inhibitors

et al. 2009

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)These authors contributed equally to the work.Received May 7, 2009 We report the crystal structures of three noncovalent retrobinding inhibitors in complex with mature cathepsin L up to resolutions of 2.5, 1.8, and 2.5 Å , respectively. These inhibitors were Bpa-(Nε-Bpa)-Lys-DArg-Tyr-Npe, Bpa-(Nε-Bpa)Lys-DArg-Phe-Npe, and Bpa-MCys-DArg-Phe-Npe, where Bpa = biphenylacetyl and Pea = N-phenylethyl. These were selected to clarify the binding mode of the biphenyl groups in the S 0 subsites because the addition of a second biphenyl does not improve potency. Examination of the symmetry-related monomers in the crystal structures revealed inhibitor-inhibitor crystal packing interactions. Molecular dynamics simulations were then used to explore the structure and dynamical behavior of the isolated protein-ligand complexes in solution. In the simulations, the backbone biphenyl groups for all three inhibitors ended up in the same location despite having started out in different orientations in the initial crystal structure conformations. The lack of improved potency of the larger inhibitors over the smaller one is attributed to a correspondingly greater entropic cost of binding.

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“…Figure 2a shows the simulated annealing F o -F c omit map for inhibitor 4. 7,8 The crystal structures of 4, 9, and 14 are reported in the current paper.…”

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

“…Binding affinities were taken from published data. 7,8 Cocrystallization and Data Collection. Inhibitor 4.…”

Section: Methodsmentioning

confidence: 99%

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A Combined Crystallographic and Molecular Dynamics Study of Cathepsin L Retrobinding Inhibitors

et al. 2009

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Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships

et al. 2017

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Falcipain-2 (FP-2) is a major hemoglobinase of Plasmodium falciparum, considered an important drug target for the development of antimalarials. A previous study reported a novel series of 20 reversible peptide-based inhibitors of FP-2. However, the lack of tridimensional structures of the complexes hinders further optimization strategies to enhance the inhibitory activity of the compounds. Here we report the prediction of the binding modes of the aforementioned inhibitors to FP-2. A computational approach combining previous knowledge on the determinants of binding to the enzyme, docking, and postdocking refinement steps, is employed. The latter steps comprise molecular dynamics simulations and free energy calculations. Remarkably, this approach leads to the identification of near-native ligand conformations when applied to a validation set of protein-ligand structures. Overall, we proposed substrate-like binding modes of the studied compounds fulfilling the structural requirements for FP-2 binding and yielding free energy values that correlated well with the experimental data. Proteins 2017; 85:1666-1683. © 2017 Wiley Periodicals, Inc.

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A comparative account of sar studies of semicarbazones and thiosemicarbazones on cathepsins H and L

Raghav

Kaur

2017

Med Chem Res

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Exploring Inhibitor Binding at the S′ Subsites of Cathepsin L

Cited by 29 publications

References 45 publications

A Combined Crystallographic and Molecular Dynamics Study of Cathepsin L Retrobinding Inhibitors

A Combined Crystallographic and Molecular Dynamics Study of Cathepsin L Retrobinding Inhibitors

Predicting binding modes of reversible peptide-based inhibitors of falcipain-2 consistent with structure-activity relationships

A comparative account of sar studies of semicarbazones and thiosemicarbazones on cathepsins H and L

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