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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Crystal Structures Of Human Ctbp In Complex With Substrate Mtob Reveal Active Site Features Useful For Inhibitor Design, Brendan Hilbert, Steven Grossman, Celia Schiffer, William Royer
Crystal Structures Of Human Ctbp In Complex With Substrate Mtob Reveal Active Site Features Useful For Inhibitor Design, Brendan Hilbert, Steven Grossman, Celia Schiffer, William Royer
Celia A. Schiffer
The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD(+) revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD(+) phosphate. Neither feature is present in other d2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors. Elsevier B.V. All …
Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer
Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer
Celia A. Schiffer
Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, …
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Decomposing The Energetic Impact Of Drug-Resistant Mutations: The Example Of Hiv-1 Protease-Drv Binding, Yufeng Cai, Celia Schiffer
Celia A. Schiffer
HIV-1 protease is a major drug target for AIDS therapy. With the appearance of drug-resistant HIV-1 protease variants, understanding the mechanism of drug resistance becomes critical for rational drug design. Computational methods can provide more details about inhibitor-protease binding than crystallography and isothermal titration calorimetry. The latest FDA-approved HIV-1 protease inhibitor is Darunavir (DRV). Herein, each DRV atom is evaluated by free energy component analysis for its contribution to the binding affinity with wild-type protease and ACT, a drug-resistant variant. This information can contribute to the rational design of new HIV-1 protease inhibitors.
Hydrophobic Core Flexibility Modulates Enzyme Activity In Hiv-1 Protease, Seema Mittal, Yufeng Cai, Madhavi Nalam, Daniel Bolon, Celia Schiffer
Hydrophobic Core Flexibility Modulates Enzyme Activity In Hiv-1 Protease, Seema Mittal, Yufeng Cai, Madhavi Nalam, Daniel Bolon, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the …
Evaluation Of The Substrate Envelope Hypothesis For Inhibitors Of Hiv-1 Protease, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Celia Schiffer, Michael Gilson
Evaluation Of The Substrate Envelope Hypothesis For Inhibitors Of Hiv-1 Protease, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Celia Schiffer, Michael Gilson
Celia A. Schiffer
Crystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggested that an inhibitor that fits within the substrate envelope should tend to evade viral resistance because a protease mutation that reduces the affinity of the inhibitor will also tend to reduce the affinity of substrate, and will hence decrease the activity of the enzyme. Accordingly, inhibitors that fit the substrate envelope better should be less susceptible to clinically observed resistant mutations, since these must also allow substrates to bind. The …
Discovery Of Hiv-1 Protease Inhibitors With Picomolar Affinities Incorporating N-Aryl-Oxazolidinone-5-Carboxamides As Novel P2 Ligands, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Madhavi Nalam, Celia Schiffer, Tariq Rana
Discovery Of Hiv-1 Protease Inhibitors With Picomolar Affinities Incorporating N-Aryl-Oxazolidinone-5-Carboxamides As Novel P2 Ligands, Akbar Ali, G. S. Kiran Kumar Reddy, Hong Cao, Saima Anjum, Madhavi Nalam, Celia Schiffer, Tariq Rana
Celia A. Schiffer
Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2' phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with K(i) values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2' phenyl ring, …
Substrate Shape Determines Specificity Of Recognition For Hiv-1 Protease: Analysis Of Crystal Structures Of Six Substrate Complexes, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Substrate Shape Determines Specificity Of Recognition For Hiv-1 Protease: Analysis Of Crystal Structures Of Six Substrate Complexes, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Celia A. Schiffer
The homodimeric HIV-1 protease is the target of some of the most effective antiviral AIDS therapy, as it facilitates viral maturation by cleaving ten asymmetric and nonhomologous sequences in the Gag and Pol polyproteins. Since the specificity of this enzyme is not easily determined from the sequences of these cleavage sites alone, we solved the crystal structures of complexes of an inactive variant (D25N) of HIV-1 protease with six peptides that correspond to the natural substrate cleavage sites. When the protease binds to its substrate and buries nearly 1000 A2 of surface area, the symmetry of the protease is broken, …
Rationale For More Diverse Inhibitors In Competition With Substrates In Hiv-1 Protease, Nevra Ozer, Celia Schiffer, Turkan Haliloglu
Rationale For More Diverse Inhibitors In Competition With Substrates In Hiv-1 Protease, Nevra Ozer, Celia Schiffer, Turkan Haliloglu
Celia A. Schiffer
The structural fluctuations of HIV-1 protease in interaction with its substrates versus inhibitors were analyzed using the anisotropic network model. The directions of fluctuations in the most cooperative functional modes differ mainly around the dynamically key regions, i.e., the hinge axes, which appear to be more flexible in substrate complexes. The flexibility of HIV-1 protease is likely optimized for the substrates' turnover, resulting in substrate complexes being dynamic. In contrast, in an inhibitor complex, the inhibitor should bind and lock down to inactivate the active site. Protease and ligands are not independent. Substrates are also more flexible than inhibitors and …
Accounting For Molecular Mobility In Structure Determination Based On Nuclear Magnetic Resonance Spectroscopic And X-Ray Diffraction Data, Wilfred Van Gunsteren, Roger Brunne, P. Gros, René Van Schaik, Celia Schiffer, Andrew Torda
Accounting For Molecular Mobility In Structure Determination Based On Nuclear Magnetic Resonance Spectroscopic And X-Ray Diffraction Data, Wilfred Van Gunsteren, Roger Brunne, P. Gros, René Van Schaik, Celia Schiffer, Andrew Torda
Celia A. Schiffer
No abstract provided.
Substrate Specificity In Hiv-1 Protease By A Biased Sequence Search Method, Nevra Ozer, Turkan Haliloglu, Celia Schiffer
Substrate Specificity In Hiv-1 Protease By A Biased Sequence Search Method, Nevra Ozer, Turkan Haliloglu, Celia Schiffer
Celia A. Schiffer
Drug resistance in HIV-1 protease can also occasionally confer a change in the substrate specificity. Through the use of computational techniques, a relationship can be determined between the substrate sequence and three-dimensional structure of HIV-1 protease, and be utilized to predict substrate specificity. In this study, we introduce a biased sequence search threading (BSST) methodology to analyze the preferences of substrate positions and correlations between them that might also identify which positions within known substrates can likely tolerate sequence variability and which cannot. The potential sequence space was efficiently explored using a low-resolution knowledge-based scoring function. The low-energy substrate sequences …
How Does A Symmetric Dimer Recognize An Asymmetric Substrate? A Substrate Complex Of Hiv-1 Protease, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
How Does A Symmetric Dimer Recognize An Asymmetric Substrate? A Substrate Complex Of Hiv-1 Protease, Moses Prabu-Jeyabalan, Ellen Nalivaika, Celia Schiffer
Celia A. Schiffer
The crystal structure of an actual HIV-1 protease-substrate complex is presented at 2.0 A resolution (R-value of 19.7 % (R(free) 23.3 %)) between an inactive variant (D25N) of HIV-1 protease and a long substrate peptide, Lys-Ala-Arg-Val-Leu-Ala-Glu-Ala-Met-Ser, which covers a full binding epitope of capsid(CA)-p2, cleavage site. The substrate peptide is asymmetric in both size and charge distribution. To accommodate this asymmetry the two protease monomers adopt different conformations burying a total of 1038 A(2) of surface area at the protease-substrate interface. The specificity for the CA-p2 substrate peptide is mainly hydrophobic, as most of the hydrogen bonds are made with …
Design Of Hiv-1 Protease Inhibitors Active On Multidrug-Resistant Virus, Dominique Surleraux, Herman De Kock, Wim Verschueren, Geert Pille, Louis Maes, Anik Peeters, Sandrine Vendeville, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Design Of Hiv-1 Protease Inhibitors Active On Multidrug-Resistant Virus, Dominique Surleraux, Herman De Kock, Wim Verschueren, Geert Pille, Louis Maes, Anik Peeters, Sandrine Vendeville, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Celia A. Schiffer
On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile …
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Dynamics Of Preferential Substrate Recognition In Hiv-1 Protease: Redefining The Substrate Envelope, Aysegul Ozen, Turkan Haliloglu, Celia Schiffer
Celia A. Schiffer
Human immunodeficiency virus type 1 (HIV-1) protease (PR) permits viral maturation by processing the gag and gag-pro-pol polyproteins. HIV-1 PR inhibitors (PIs) are used in combination antiviral therapy but the emergence of drug resistance has limited their efficacy. The rapid evolution of HIV-1 necessitates consideration of drug resistance in novel drug design. Drug-resistant HIV-1 PR variants no longer inhibited efficiently, continue to hydrolyze the natural viral substrates. Though highly diverse in sequence, the HIV-1 PR substrates bind in a conserved three-dimensional shape we termed the substrate envelope. Earlier, we showed that resistance mutations arise where PIs protrude beyond the substrate …
Cooperative Fluctuations Of Unliganded And Substrate-Bound Hiv-1 Protease: A Structure-Based Analysis On A Variety Of Conformations From Crystallography And Molecular Dynamics Simulations, Nese Kurt, Walter Scott, Celia Schiffer, Turkan Haliloglu
Cooperative Fluctuations Of Unliganded And Substrate-Bound Hiv-1 Protease: A Structure-Based Analysis On A Variety Of Conformations From Crystallography And Molecular Dynamics Simulations, Nese Kurt, Walter Scott, Celia Schiffer, Turkan Haliloglu
Celia A. Schiffer
The dynamics of HIV-1 protease, both in unliganded and substrate-bound forms have been analyzed by using an analytical method, Gaussian network model (GNM). The method is applied to different conformations accessible to the protein backbone in the native state, observed in crystal structures and snapshots from fully atomistic molecular dynamics (MD) simulation trajectories. The modes of motion obtained from GNM on different conformations of HIV-1 protease are conserved throughout the MD simulations. The flaps and 40's loop of the unliganded HIV-1 protease structure are identified as the most mobile regions. However, in the liganded structure these flaps lose mobility, and …
Simultaneous Refinement Of The Structure Of Bpti Against Nmr Data Measured In Solution And X-Ray Diffraction Data Measured In Single Crystals, Celia Schiffer, Robert Huber, Kurt Wuthrich, Wilfred Van Gunsteren
Simultaneous Refinement Of The Structure Of Bpti Against Nmr Data Measured In Solution And X-Ray Diffraction Data Measured In Single Crystals, Celia Schiffer, Robert Huber, Kurt Wuthrich, Wilfred Van Gunsteren
Celia A. Schiffer
The structure of the bovine pancreatic trypsin inhibitor (BPTI) has been determined to high resolution by both NMR spectroscopy in solution and X-ray diffraction in crystals. The root-mean-square difference calculated between the two structures for the polypeptide backbone is 0.9 A. Several amino acid side-chains, of which all but one are charged or polar, have different conformations. We find that by refining one structure simultaneously against both the NMR and crystallographic data sets, it can accommodate both. Different starting configurations were used, including the X-ray structure 5pti, an NMR conformer, and the X-ray structure in the full unit cell with …
Computational Design And Experimental Study Of Tighter Binding Peptides To An Inactivated Mutant Of Hiv-1 Protease, Michael Altman, Ellen Nalivaika, Moses Prabu-Jeyabalan, Celia Schiffer, Bruce Tidor
Computational Design And Experimental Study Of Tighter Binding Peptides To An Inactivated Mutant Of Hiv-1 Protease, Michael Altman, Ellen Nalivaika, Moses Prabu-Jeyabalan, Celia Schiffer, Bruce Tidor
Celia A. Schiffer
Drug resistance in HIV-1 protease, a barrier to effective treatment, is generally caused by mutations in the enzyme that disrupt inhibitor binding but still allow for substrate processing. Structural studies with mutant, inactive enzyme, have provided detailed information regarding how the substrates bind to the protease yet avoid resistance mutations; insights obtained inform the development of next generation therapeutics. Although structures have been obtained of complexes between substrate peptide and inactivated (D25N) protease, thermodynamic studies of peptide binding have been challenging due to low affinity. Peptides that bind tighter to the inactivated protease than the natural substrates would be valuable …
Evaluating The Substrate-Envelope Hypothesis: Structural Analysis Of Novel Hiv-1 Protease Inhibitors Designed To Be Robust Against Drug Resistance, Madhavi Nalam, Akbar Ali, Michael Altman, G. S. Kiran Kumar Reddy, Sripriya Chellappan, Visvaldas Kairys, Aysegul Ozen, Hong Cao, Michael Gilson, Bruce Tidor, Tariq Rana, Celia Schiffer
Evaluating The Substrate-Envelope Hypothesis: Structural Analysis Of Novel Hiv-1 Protease Inhibitors Designed To Be Robust Against Drug Resistance, Madhavi Nalam, Akbar Ali, Michael Altman, G. S. Kiran Kumar Reddy, Sripriya Chellappan, Visvaldas Kairys, Aysegul Ozen, Hong Cao, Michael Gilson, Bruce Tidor, Tariq Rana, Celia Schiffer
Celia A. Schiffer
Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type …
Structure Of A Phage Display-Derived Variant Of Human Growth Hormone Complexed To Two Copies Of The Extracellular Domain Of Its Receptor: Evidence For Strong Structural Coupling Between Receptor Binding Sites, Celia Schiffer, Mark Ultsch, Scott Walsh, William Somers, Abraham De Vos, Anthony Kossiakoff
Structure Of A Phage Display-Derived Variant Of Human Growth Hormone Complexed To Two Copies Of The Extracellular Domain Of Its Receptor: Evidence For Strong Structural Coupling Between Receptor Binding Sites, Celia Schiffer, Mark Ultsch, Scott Walsh, William Somers, Abraham De Vos, Anthony Kossiakoff
Celia A. Schiffer
The structure of the ternary complex between the phage display- optimized, high-affinity Site 1 variant of human growth hormone (hGH) and two copies of the extracellular domain (ECD) of the hGH receptor (hGHR) has been determined at 2.6 A resolution. There are widespread and significant structural differences compared to the wild-type ternary hGH hGHR complex. The hGH variant (hGH(v)) contains 15 Site 1 mutations and binds>10(2) tighter to the hGHR ECD (hGH(R1)) at Site 1. It is biologically active and specific to hGHR. The hGH(v) Site 1 interface is somewhat smaller and 20% more hydrophobic compared to the wild-type …
Hiv-1 Protease Inhibitors From Inverse Design In The Substrate Envelope Exhibit Subnanomolar Binding To Drug-Resistant Variants, Michael Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Michael Gilson, Celia Schiffer, Tariq Rana, Bruce Tidor
Hiv-1 Protease Inhibitors From Inverse Design In The Substrate Envelope Exhibit Subnanomolar Binding To Drug-Resistant Variants, Michael Altman, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Sripriya Chellappan, Visvaldas Kairys, Miguel Fernandes, Michael Gilson, Celia Schiffer, Tariq Rana, Bruce Tidor
Celia A. Schiffer
The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the …
The Effect Of Clade-Specific Sequence Polymorphisms On Hiv-1 Protease Activity And Inhibitor Resistance Pathways, Rajintha Bandaranayake, Madhavi Kolli, Nancy King, Ellen Nalivaika, Annie Heroux, Junko Kakizawa, Wataru Sugiura, Celia Schiffer
The Effect Of Clade-Specific Sequence Polymorphisms On Hiv-1 Protease Activity And Inhibitor Resistance Pathways, Rajintha Bandaranayake, Madhavi Kolli, Nancy King, Ellen Nalivaika, Annie Heroux, Junko Kakizawa, Wataru Sugiura, Celia Schiffer
Celia A. Schiffer
The majority of HIV-1 infections around the world result from non-B clade HIV-1 strains. The CRF01_AE (AE) strain is seen principally in Southeast Asia. AE protease differs by approximately 10% in amino acid sequence from clade B protease and carries several naturally occurring polymorphisms that are associated with drug resistance in clade B. AE protease has been observed to develop resistance through a nonactive-site N88S mutation in response to nelfinavir (NFV) therapy, whereas clade B protease develops both the active-site mutation D30N and the nonactive-site mutation N88D. Structural and biochemical studies were carried out with wild-type and NFV-resistant clade B …
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Lack Of Synergy For Inhibitors Targeting A Multi-Drug-Resistant Hiv-1 Protease, Nancy King, Laurence Melnick, Moses Prabu-Jeyabalan, Ellen Nalivaika, Shiow-Shong Yang, Yun Gao, Xiaoyi Nie, Charles Zepp, Donald Heefner, Celia Schiffer
Celia A. Schiffer
The three-dimensional structures of indinavir and three newly synthesized indinavir analogs in complex with a multi-drug-resistant variant (L63P, V82T, I84V) of HIV-1 protease were determined to approximately 2.2 A resolution. Two of the three analogs have only a single modification of indinavir, and their binding affinities to the variant HIV-1 protease are enhanced over that of indinavir. However, when both modifications were combined into a single compound, the binding affinity to the protease variant was reduced. On close examination, the structural rearrangements in the protease that occur in the tightest binding inhibitor complex are mutually exclusive with the structural rearrangements …
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Celia A. Schiffer
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high …
Structure-Based Design, Synthesis, And Structure-Activity Relationship Studies Of Hiv-1 Protease Inhibitors Incorporating Phenyloxazolidinones, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Celia Schiffer, Tariq Rana
Structure-Based Design, Synthesis, And Structure-Activity Relationship Studies Of Hiv-1 Protease Inhibitors Incorporating Phenyloxazolidinones, Akbar Ali, G. S. Kiran Kumar Reddy, Madhavi Nalam, Saima Anjum, Hong Cao, Celia Schiffer, Tariq Rana
Celia A. Schiffer
A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different phenyloxazolidinone P2 ligands were designed and synthesized. Variation of phenyl substitutions at the P2 and P2' moieties significantly affected the binding affinity and antiviral potency of the inhibitors. In general, compounds with 2- and 4-substituted phenyloxazolidinones at P2 exhibited lower binding affinities than 3-substituted analogues. Crystal structure analyses of ligand-enzyme complexes revealed different binding modes for 2- and 3-substituted P2 moieties in the protease S2 binding pocket, which may explain their different binding affinities. Several compounds with 3-substituted P2 moieties demonstrated picomolar binding affinity and low nanomolar …