title: Structure-based and property-compliant library design of 11β-HSD1 adamantyl amide inhibitors.
abstract: Multiproperty lead optimization that satisfies multiple biological endpoints remains a challenge in the pursuit of viable drug candidates. Optimization of a given lead compound to one having a desired set of molecular attributes often involves a lengthy iterative process that utilizes existing information, tests hypotheses, and incorporates new data. Within the context of a data-rich corporate setting, computational tools and predictive models have provided the chemists a means for facilitating and streamlining this iterative design process. This chapter discloses an actual library design scenario for following up a lead compound that inhibits 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The application of computational tools and predictive models in the targeted library design of adamantyl amide 11β-HSD1 inhibitors is described. Specifically, the multiproperty profiling using our proprietary PGVL (Pfizer Global Virtual Library) Hub is discussed in conjunction with the structure-based component of the library design using our in-house docking tool AGDOCK. The docking simulations were based on a piecewise linear potential energy function in combination with an efficient evolutionary programming search engine. The library production protocols and results are also presented.
authors.affiliation: Cancer Crystallography & Computational Chemistry, La Jolla Laboratories, Pfizer Inc., San Diego, CA, USA.
authors.forename: Genevieve D
authors.initials: GD
authors.lastname: Paderes
authors.forename: Klaus
authors.initials: K
authors.lastname: Dress
authors.forename: Buwen
authors.initials: B
authors.lastname: Huang
authors.forename: Jeff
authors.initials: J
authors.lastname: Elleraas
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.forename: Tom
authors.initials: T
authors.lastname: Pauly
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000218:Adamantane / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane