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1.  Joint X-ray/neutron crystallographic study of HIV-1 protease with clinical inhibitor amprenavir – insights for drug design 
Journal of medicinal chemistry  2013;56(13):10.1021/jm400684f.
HIV-1 protease is an important target for the development of antiviral inhibitors to treat AIDS. A room-temperature joint X-ray/neutron structure of the protease in complex with clinical drug amprenavir has been determined at 2.0 Å resolution. The structure provides direct determination of hydrogen atom positions in the enzyme active site. Analysis of the enzyme-drug interactions suggests that some hydrogen bonds may be weaker than deduced from the non-hydrogen interatomic distances. This information may be valuable for the design of improved protease inhibitors.
doi:10.1021/jm400684f
PMCID: PMC3815997  PMID: 23772563
neutron diffraction; HIV-1 protease; enzyme-drug complex; amprenavir; drug design
2.  Extreme multidrug resistant HIV-1 protease with 20 mutations is resistant to novel protease inhibitors with P1′-pyrrolidinone or P2-tris-tetrahydrofuran 
Journal of medicinal chemistry  2013;56(10):4017-4027.
Extreme drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with the clinical inhibitor amprenavir (1) and two potent antiviral investigational inhibitors GRL-02031 (2) and GRL-0519 (3). Clinical inhibitors are >1000-fold less active on PR20 than on wild type enzyme, which is consistent with dissociation constants (KL) from isothermal titration calorimetry of 40 nM for 3, 178 nM for amprenavir, and 960 nM for 2. High resolution crystal structures of PR20-inhibitor complexes revealed altered interactions compared with the corresponding wild-type PR complexes in agreement with relative inhibition. Amprenavir lacks interactions due to PR20 mutations in the S2/S2′ subsites relative to PR. Inhibitors 2 and 3 lose interactions with Arg8′ in PR20 relative to the wild type enzyme since Arg8′ shifts to interact with mutated L10F side chain. Overall, inhibitor 3 compares favorably with darunavir in affinity for PR20 and shows promise for further development.
doi:10.1021/jm400231v
PMCID: PMC3719844  PMID: 23590295
HIV/AIDS; aspartic protease; X-ray crystallography; drug resistance
3.  Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease 
Journal of medicinal chemistry  2013;56(3):1074-1083.
GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PRR8Q, PRD30N, PRI50V, PRI54M, and PRV82A were analyzed in relation to kinetic data. The smaller valine side chain in PRI50V eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PRD30N showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PRR8Q replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.
doi:10.1021/jm301519z
PMCID: PMC3574189  PMID: 23298236
HIV / AIDS; aspartic protease; X-ray crystallography; drug resistance
4.  Structure-Based Design of Highly Selective β-Secretase Inhibitors: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Crystal Structure 
Journal of medicinal chemistry  2012;55(21):9195-9207.
Structure-based design, synthesis and X-ray structure of protein-ligand complexes of exceptionally potent and selective β-secretase inhibitors are described. The inhibitors are designed specifically to interact with S1′ active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 5 has exhibited exceedingly potent inhibitory activity (Ki = 17 pM) and high selectivity over BACE 2 (>7,000-fold) and cathepsin D (>250,000-fold). A protein-ligand crystal structure revealed important molecular insight into these selectivities. These interactions may serve as an important guide to design selectivity over the physiologically important aspartic acid proteases.
doi:10.1021/jm3008823
PMCID: PMC3493683  PMID: 22954357
5.  Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1′-pyrrolidinone ring 
Journal of Medicinal Chemistry  2012;55(7):3387-3397.
GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1′ (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25 to 1.55 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PRI47V, PRL76V, PRV82A and PRN88D. Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PRI47V and PRL76V, and the altered charge of PRN88D are associated with significant local structural changes compared to the wild-type PRWT, while substitution of alanine in PRV82A increases the size of the S1′ subsite. The P1′ pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PRWT with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.
doi:10.1021/jm300072d
PMCID: PMC3355519  PMID: 22401672
aspartic protease; X-ray crystallography; molecular recognition; drug resistance; drug design
6.  Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Crystal Structure 
Journal of medicinal chemistry  2011;54(16):5890-5901.
We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor-bound HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethyl sulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core, displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions.
doi:10.1021/jm200649p
PMCID: PMC3164320  PMID: 21800876
7.  Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-derived High Affinity P2 ligands: Structure-activity Studies and Biological Evaluation 
Journal of medicinal chemistry  2010;54(2):622-634.
The design, synthesis, and evaluation of a new series of hexahydrofuropyran-derived HIV-1 protease inhibitors are described. We have designed a stereochemically defined hexahydrofuropyranol-derived urethane as the P2-ligand. The current ligand is designed based upon the X-ray structure of 1a-bound HIV-1 protease. The synthesis of (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b] pyran-4-ol (−)-7 was carried out in optically active form. Incorporation of this ligand provided inhibitor 35a, which has shown excellent enzyme inhibitory activity and antiviral potency. Our structure activity studies have indicated that the stereochemistry and the position of oxygens in the ligand are important to the observed potency of the inhibitor. Inhibitor 35a has maintained excellent potency against multidrug-resistant HIV-1 variants. An active site model of 35a was created based upon the X-ray structure of 1b-bound HIV-1 protease. The model offers molecular insights regarding ligand-binding site interactions of the hexahydrofuropyranol-derived novel P2-ligand.
doi:10.1021/jm1012787
PMCID: PMC3024462  PMID: 21194227
8.  Structure-Based Design, Synthesis, and Biological Evaluation of a Series of Novel and Reversible Inhibitors for the Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease 
Journal of medicinal chemistry  2009;52(16):5228-5240.
We describe here the design, synthesis, molecular modeling, and biological evaluation of a series of small molecule, nonpeptide inhibitors of SARS-CoV PLpro. Our initial lead compound was identified via high-throughput screening of a diverse chemical library. We subsequently carried out structure-activity relationship studies, and optimized the lead structure to potent inhibitors that have shown antiviral activity against SARS-CoV infected Vero E6 cells. Based upon the X-ray crystal structure of one of the potent inhibitors 24-bound to SARS-CoV PLpro, a drug-design template was created. Our structure-based modification led to the design of a more potent inhibitor, 2 (enzyme IC50 = 0.46 μM; antiviral EC50 = 12.5 μM). Interestingly, its methylamine derivative 49 displayed good enzyme inhibitory potency (IC50 = 1.3 μM) and most potent SARS antiviral activity (EC50 = 2.5 μM) in the series. We have carried out computational docking studies and generated a predictive 3D-QSAR model for SARS-CoV PLpro inhibitors.
doi:10.1021/jm900611t
PMCID: PMC3148848  PMID: 19645480
9.  Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Novel Protease Inhibitors: Design, Synthesis, Protein-Ligand X-ray Structure and Biological Evaluation 
Journal of medicinal chemistry  2010;53(13):4968-4979.
The design, synthesis, X-ray crystal structure, molecular modeling, and biological evaluation of a series of new generation SARS-CoV PLpro inhibitors are described. A new lead compound 3 (6577871) was identified via high-throughput screening of a diverse chemical library. Subsequently, we carried out lead optimization and structure-activity studies to provide a series of improved inhibitors that show potent PLpro inhibition and antiviral activity against SARS-CoV infected Vero E6 cells. Interestingly, the (S)-Me inhibitor 15h (enzyme IC50 = 0.56 μM; antiviral EC50 = 9.1 μM) and the corresponding (R)-Me 15g (IC50 = 0.32 μM; antiviral EC50 = 9.1 μM) are the most potent compounds in this series, with nearly equivalent enzymatic inhibition and antiviral activity. A protein-ligand X-ray structure of 15g-bound SARS-CoV PLpro and a corresponding model of 15h docked to PLpro provide intriguing molecular insight into the ligand-binding site interactions.
doi:10.1021/jm1004489
PMCID: PMC2918394  PMID: 20527968
10.  Susceptibility of Potent Antiviral Inhibitor to Highly Drug Resistant Mutations D30N, I50V and L90M of HIV-1 Protease 
Journal of medicinal chemistry  2006;49(4):1379-1387.
The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V and L90M that provide resistance to the major clinical inhibitors. The inhibition constants (Ki) of TMC-114 for mutants PRD30N, PRI50V, and PRL90M were 30-, 9- and 0.14-fold, respectively, relative to wild type PR. The molecular basis for the inhibition was analyzed using high resolution (1.22–1.45 Å) crystal structures of PR mutant complexes with TMC-114. In PRD30N the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PRI50V the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PRL90M structure compared to the PR structure leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.
doi:10.1021/jm050943c
PMCID: PMC3015180  PMID: 16480273
HIV-1; protease inhibitor; crystal structure; enzyme kinetics; hydrogen bonds
11.  Design, Synthesis, Protein-ligand X-ray Structures and Biological Evaluation of a Series of Novel Macrocyclic HIV-1 Protease Inhibitors to Combat Drug-resistance 
Journal of medicinal chemistry  2009;52(23):7689-7705.
The structure-based design, synthesis and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1′ S2′ subsites and retain all major hydrogen bonding with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogs and a preference for 10 and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in the reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity and they exerted potent activity against multi-drug resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.
doi:10.1021/jm900695w
PMCID: PMC2943150  PMID: 19746963
12.  Design of HIV-1 Protease Inhibitors with Pyrrolidinones and Oxazolidinones as Novel P1’-Ligands to Enhance Backbone-binding interactions with Protease: Synthesis, Biological Evaluation and Protein-ligand X-ray Studies 
Journal of medicinal chemistry  2009;52(13):3902-3914.
Structure-based design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidinone and methyl oxazolidinone as the P1′-ligands. These ligands are designed to interact with Gly-27′ carbonyl and Arg-8 side chain in the S1′-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with an (S)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. Inhibitor 19b maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b–bound HIV-1 protease revealed that the P1′-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1’ and S2-subsites of HIV-1 protease.
doi:10.1021/jm900303m
PMCID: PMC2745609  PMID: 19473017
14.  Flexible Cyclic Ethers/Polyethers as Novel P2-Ligands for HIV-1 Protease Inhibitors: Design, Synthesis, Biological Evaluation and Protein-ligand X-ray Studies 
Journal of medicinal chemistry  2008;51(19):6021.
We report the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors. The inhibitors incorporate stereochemically defined flexible cyclic ethers/polyethers as the high affinity P2-ligands. Inhibitors containing small ring 1,3-dioxacycloalkanes have shown potent enzyme inhibitory and antiviral activity. Inhibitors 3d and 3h are the most active inhibitors. Inhibitor 3d maintains excellent potency against a variety of multi-PI-resistant clinical strains. Our structure-activity studies indicate that the ring size, stereochemistry, and position of oxygens are important for the observed activity. Optically active synthesis of 1,3-dioxepan-5-ol along with the syntheses of various cyclic ether and polyether ligands have been described. A protein-ligand X-ray crystal structure of 3d-bound HIV-1 protease was determined. The structure revealed that the P2-ligand makes extensive interactions including hydrogen bonding with the protease backbone in the S2-site. In addition, the P2-ligand in 3d forms a unique water-mediated interaction with the NH of Gly-48.
doi:10.1021/jm8004543
PMCID: PMC2812926  PMID: 18783203
15.  Solution Kinetics Measurements Suggest HIV-1 Protease Has Two Binding Sites for Darunavir and Amprenavir 
Journal of medicinal chemistry  2008;51(20):6599-6603.
Darunavir, a potent antiviral drug, showed an unusual second binding site on the HIV-1 protease dimer surface of the V32I drug resistant mutant and normal binding in the active site cavity. Kinetic analysis for wild type and mutant protease showed mixed-type competitive-uncompetitive inhibition for darunavir and the chemically related amprenavir, while saquinavir showed competitive inhibition. The inhibition model is consistent with the observed second binding site for darunavir and helps to explain its antiviral potency.
doi:10.1021/jm800283k
PMCID: PMC2771923  PMID: 18808097
16.  Potent New Antiviral Compound Shows Similar Inhibition and Structural Interactions with Drug Resistant Mutants and Wild Type HIV-1 Protease 
Journal of medicinal chemistry  2007;50(18):4509-4515.
The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A and I84V that provide resistance to the major clinical inhibitors. Compound 1 had inhibition constants of 17-fold, 8-fold, 3-fold and 3-fold, respectively, for PRD30N, PRI50V, PRV82A and PRI84V relative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PRD30N, where inhibitor 1 was approximately threefold less potent. The high resolution (1.11–1.60 Å) crystal structures of PR mutant complexes with inhibitor 1 showed small changes relative to the wild type enzyme. PRD30N and PRV82A showed compensating interactions with inhibitor 1 relative to those of PR, while reduced hydrophobic contacts were observed with PRI50V and PRI84V. Importantly, inhibitor 1 complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1 is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV.
doi:10.1021/jm070482q
PMCID: PMC2751596  PMID: 17696515
HIV-1; protease inhibitor; GRL-98065; crystal structure; enzyme kinetics; hydrogen bonds

Results 1-16 (16)