Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
Ghosh
A K
AK
Department of Chemistry, University of Illinois at Chicago 60607, USA.
Kincaid
J F
JF
Walters
D E
DE
Chen
Y
Y
Chaudhuri
N C
NC
Thompson
W J
WJ
Culberson
C
C
Fitzgerald
P M
PM
Lee
H Y
HY
McKee
S P
SP
Munson
P M
PM
Duong
T T
TT
Darke
P L
PL
Zugay
J A
JA
Schleif
W A
WA
Axel
M G
MG
Lin
J
J
Huff
J R
JR
D000595:Amino Acid Sequence; D001224:Aspartic Acid; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D006860:Hydrogen Bonding; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009904:Optical Rotation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D005663:Furans; D017320:HIV Protease Inhibitors; D008024:Ligands; D001224:Aspartic Acid; C018674:tetrahydrofuran; D016333:HIV Protease