Discovery and optimization of nonpeptide HIV-1 protease inhibitors (original) (raw)
Related papers
Journal of Medicinal Chemistry, 2012
A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants, in particular inhibitors containing 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K i values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp-29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies.
Design, synthesis, and conformational analysis of a novel series of HIV protease inhibitors
Bioorganic & Medicinal Chemistry Letters, 1998
A combination of structure-based design and both solution, and solid-phase synthesis were utilized to derive a potent (nM) series of HIV-1 protease inhibitors bearing a structurally novel backbone. Detailed structural analysis of several inhibitors prepared in this series has suggested that rigidification of the PI/P2 region of this class of molecules may result in compounds with improved potency.
Journal of Medicinal Chemistry, 1994
HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains a n important goal. Using a n HN-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-W-l-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affhity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)buty1l-W-l-benzopyran-2-one (31).
The Journal of biological chemistry, 1993
A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional structure determination. The initial compound, haloperidol, was discovered through computational screening of the Cambridge Structural Database using a shape complementarity algorithm. The subsequent modification is a non-peptidic lateral lead, which belongs to a family of compounds with well characterized pharmacological properties. This thioketal derivative of haloperidol and a halide counterion are bound within the enzyme active site in a mode distinct from the observed for peptide-based inhibitors. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based search. The structures provide the context for subsequent synthetic modifications of the inhibitor.
Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance
J. Med. …, 2006
Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PIresistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 Å resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
INHIBITORS OF HIV-1 PROTEASE: A Major Success of Structure-Assisted Drug Design 1
Annual Review of Biophysics and Biomolecular Structure, 1998
Retroviral protease (PR) from the human immunodeficiency virus type 1 (HIV-1) was identified over a decade ago as a potential target for structure-based drug design. This effort was very successful. Four drugs are already approved, and others are undergoing clinical trials. The techniques utilized in this remarkable example of structure-assisted drug design included crystallography, NMR, computational studies, and advanced chemical synthesis. The development of these drugs is discussed in detail. Other approaches to designing HIV-1 PR inhibitors, based on the concepts of symmetry and on the replacement of a water molecule that had been found tetrahedrally coordinated between the enzyme and the inhibitors, are also discussed. The emergence of drug-induced mutations of HIV-1 PR leads to rapid loss of potency of the existing drugs and to the need to continue the development process. The structural basis of drug resistance and the ways of overcoming this phenomenon are mentioned.
HIV-1 protease inhibitors containing a novel C2 symmetrical hydroxyalkylgem-diamino core structure
The Journal of Peptide Research, 2009
Two series of peptidomimetics containing a novel C, symmetrical hydroxyalkylgem-diamino core structure were prepared, from amino acid starting materials, and evaluated as inhibitors of HIV-1 protease (HIV-1 Pr). l,l-Diamino-3-hydroxypropane (gHse) derivatives showed weak inhibitory potency (IC,, > 10 PM). In the l,l-diamino-2-hydroxyethane (gSer) series. a compound containing PljPl ' benzyl and P2/P2' Fmoc substituents, displayed a significant HIV-1 Pr inhibition (IC50=440 nM). 0 Munksgaard 1997.
Bioorganic & Medicinal Chemistry, 1999
ÐThe structure±activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing a-hydroxy-b-amino acids is discussed. We demonstrated that substituent groups on the P 1 aromatic rings of the inhibitors exert signi®cant in¯uence on their biological activity. Inhibitors bearing an alkyl or a¯uorine atom at the meta and para position on their P 1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P 2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent {IC 90 (CEM/HIV-1 IIIB) 27 nM} and showed good pharmacokinetics in rats.