title: Structure-guided, target-based drug discovery - exploiting genome information from HIV to mycobacterial infections.
abstract: The use of protein crystallography in structure-guided drug discovery allows identification of potential inhibitor-binding sites and optimisation of interactions of hits and lead compounds with a target protein. An early example of this approach was the use of the structure of HIV protease in designing AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design. Here, we discuss the use of structure-guided target identification and lead optimisation using fragment-based approaches in the development of new antimicrobials for mycobacterial infections.
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.
authors.forename: Sony
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.
authors.forename: Sherine E
authors.initials: SE
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ochoa Montano
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, UK.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D003461:Crystallography; D055808:Drug Discovery / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D009164:Mycobacterium Infections / Q000188:drug therapy; D011487:Protein Conformation; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D011506:Proteins
keywords: HIV protease; Mycobacterium abscessus; Mycobacterium tuberculosis; drug design/discovery; fragment-based; inhibitors; structure-guided