Principles of Enzyme‐Inhibitor Design

Banner, David W.

doi:10.1002/3527601813.ch7

Cited by 7 publications

(12 citation statements)

References 52 publications

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“…Most active site direct inhibitors were developed based on the described αTh-PPACK complex [5], [57]. Despite of the wealth of structural information since the elucidation of the αTh crystal structure [1], [3], approval of direct thrombin inhibitors for clinical use is very recent.…”

Section: Discussionmentioning

confidence: 99%

“…From this large database, no large conformational changes are observed [5]. Only limited overall changes with global deviations on the order of about 1 Å and some limited local shifts in loops of small secondary structure elements are seen.…”

Section: Introductionmentioning

confidence: 88%

“…The crystal structure of αTh was elucidated more than 20 years ago [1] ; since then more than 300 crystal structures have been reported so far, including complexes with various ligands, structures solved under varying chemical conditions such as pH, precipitants and coadjuvants, mutants designed to abrogate the autoproteolytic degradation [2] , [3] and the wild-type recombinant human αTh in the absence of Na + ions [4] . From this large database, no large conformational changes are observed [5] . Only limited overall changes with global deviations on the order of about 1 Å and some limited local shifts in loops of small secondary structure elements are seen.…”

Section: Introductionmentioning

confidence: 95%

“…In the present work, we performed a comparative analysis between αTh in the free form and in the bound state in solution. To address this issue we used D-Phe-Pro-Arg-chloromethyl ketone (PPACK), a selective αTh inhibitor [9] , which has long been used as a template in designing drugs that target αTh [5] . We have combined small-angle X-ray scattering, molecular dynamics simulations and equilibrium and kinetic folding thermodynamic measurements to dissect the energetics and molecular features of αTh and αTh-PPACK.…”

Section: Introductionmentioning

confidence: 99%

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Structure and Behavior of Human α-Thrombin upon Ligand Recognition: Thermodynamic and Molecular Dynamics Studies

et al. 2011

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Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Structure and Behavior of Human α-Thrombin upon Ligand Recognition: Thermodynamic and Molecular Dynamics Studies

et al. 2011

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“…The most dramatic improvement (>1000-fold) is achieved when the only weakly active pyrrole 20b is converted into 3-methylpyrrole 20f. The importance of optimally filling small voids in buried cavities has been noted previously [38,39]. This optimi-zation concept is nicely exemplified on DPP-IV, with a steep SAR for S1 pocket substituents.…”

Section: S1 Pocketmentioning

confidence: 91%

Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

Kuhn

Hennig²,

Mattei

2007

CTMC

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The serine protease dipeptidyl peptidase IV (DPP-IV) is a clinically validated target for the treatment of type II diabetes and has received considerable interest from the pharmaceutical industry over the last years. Concomitant with a large variety of published small molecule DPP-IV inhibitors almost twenty co-crystal structures have been released to the public as of May 2006. In this review, we discuss the structural characteristics of the DPP-IV binding site and use the available X-ray information together with published structure-activity relationship data to identify the molecular interactions that are most important for tight enzyme-inhibitor binding. Optimized interactions with the two key recognition motifs, i.e. the lipophilic S1 pocket and the negatively charged Glu 205/206 pair, result in large gains in binding free energy, which can be further improved by additional favorable contacts to side chains that flank the active site. First examples show that the lessons learned from the X-ray structures can be successfully incorporated into the design of novel DPP-IV inhibitors.

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A Real-World Perspective on Molecular Design

et al. 2016

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We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.

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Principles of Enzyme‐Inhibitor Design

Cited by 7 publications

References 52 publications

Structure and Behavior of Human α-Thrombin upon Ligand Recognition: Thermodynamic and Molecular Dynamics Studies

Structure and Behavior of Human α-Thrombin upon Ligand Recognition: Thermodynamic and Molecular Dynamics Studies

Molecular Recognition of Ligands in Dipeptidyl Peptidase IV

A Real-World Perspective on Molecular Design

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