Abstract
Pin1 is a member of the cis-trans peptidyl-prolyl isomerase family with potential anti-cancer therapeutic value. Here we report structure-based de novo design and optimization of novel Pin1 inhibitors. Without a viable lead from internal screenings, we designed a series of novel Pin1 inhibitors by interrogating and exploring a protein crystal structure of Pin1. The ligand efficiency of the initial concept molecule was optimized with integrated SBDD and parallel chemistry approaches, resulting in a more attractive lead series.
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Combinatorial Chemistry Techniques
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Computer Simulation
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Crystallography, X-Ray
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Drug Design
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Humans
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NIMA-Interacting Peptidylprolyl Isomerase
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Peptidylprolyl Isomerase / antagonists & inhibitors*
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Peptidylprolyl Isomerase / metabolism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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NIMA-Interacting Peptidylprolyl Isomerase
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PIN1 protein, human
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Peptidylprolyl Isomerase