title: Prospective CCR5 small molecule antagonist compound design using a combined mutagenesis/modeling approach.
abstract: The viral resistance of marketed antiviral drugs including the emergence of new viral resistance of the only marketed CCR5 entry inhibitor, maraviroc, makes it necessary to develop new CCR5 allosteric inhibitors. A mutagenesis/modeling approach was used (a) to remove the potential hERG liability in an otherwise very promising series of compounds and (b) to design a new class of compounds with an unique mutant fingerprint profile depending on residues in the N-terminus and the extracellular loop 2. On the basis of residues, which were identified by mutagenesis as key interaction sites, binding modes of compounds were derived and utilized for compound design in a prospective manner. The compounds were then synthesized, and in vitro evaluation not only showed that they had good antiviral potency but also fulfilled the requirement of low hERG inhibition, a criterion necessary because a potential approved drug would be administered chronically. This work utilized an interdisciplinary approach including medicinal chemistry, molecular biology, and computational chemistry merging the structural requirements for potency with the requirements of an acceptable in vitro profile for allosteric CCR5 inhibitors. The obtained mutant fingerprint profiles of CCR5 inhibitors were used to translate the CCR5 allosteric binding site into a general pharmacophore, which can be used for discovering new inhibitors.
authors.affiliation: Department of Medicinal Chemistry, Genzyme Corporation, 153 Second Avenue, Waltham, Massachusetts 02451, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.forename: Elyse
authors.initials: E
authors.lastname: Bourque
authors.forename: Jean
authors.initials: J
authors.lastname: Labrecque
authors.forename: Sanjay J
authors.initials: SJ
authors.lastname: Danthi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langille
authors.forename: Curtis
authors.initials: C
authors.lastname: Harwig
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Darkes
authors.forename: Gloria
authors.initials: G
authors.lastname: Lau
authors.forename: Zefferino
authors.initials: Z
authors.lastname: Santucci
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bridger
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
authors.forename: Renato T
authors.initials: RT
authors.lastname: Skerlj
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D016296:Mutagenesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D051638:Ether-A-Go-Go Potassium Channels; D014508:Urea