The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Arun K Ghosh - One of the best experts on this subject based on the ideXlab platform.

  • structural studies of antiviral inhibitor with hiv 1 Protease bearing drug resistant substitutions of v32i i47v and v82i
    Biochemical and Biophysical Research Communications, 2019
    Co-Authors: Shrikant Pawar, Arun K Ghosh, Johnson Agniswamy, Y F Wang, Andres Wongsam, Robert W Harrison, Irene T. Weber
    Abstract:

    Abstract HIV-1 Protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 Protease with drug resistant mutations of V32I, I47V and V82I (PRTri) that model the inhibitor-binding site of HIV-2 Protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type Protease, however, the measured inhibition constants for PRTri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PRTri mutant in complex with inhibitor 1 at 1.5 A resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

  • Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies
    2018
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro Hattori, Hiroaki Mitsuya
    Abstract:

    We have designed, synthesized, and evaluated a new class of potent HIV-1 Protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 Protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 Protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored

  • Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis
    2018
    Co-Authors: Arun K Ghosh, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Masayuki Amano, Kanury V S Rao, Manabu Aoki, Satish Kovela, Margherita Brindisi, Yuanfang Wang
    Abstract:

    The design, synthesis, and biological evaluation of a new class of HIV-1 Protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand–backbone interactions in the Protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson–Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease revealed extensive interactions with the backbone atoms of HIV-1 Protease and provided molecular insight into the binding properties of these new inhibitors

  • design and development of highly potent hiv 1 Protease inhibitors with a crown like oxotricyclic core as the p2 ligand to combat multidrug resistant hiv variants
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Arun K Ghosh, Cuthbert D Martyr, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Yuanfang Wang, Kanury V S Rao, Manabu Aoki, Hironori Hayashi, Haydar Bulut
    Abstract:

    Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 Protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease revealed extensive interactions with the backbone atoms of HIV-1 Protease and provided molecular insight into the binding properties of these new inhibitors.

  • recent progress in the development of hiv 1 Protease inhibitors for the treatment of hiv aids
    Journal of Medicinal Chemistry, 2016
    Co-Authors: Arun K Ghosh, Heather L Osswald, Gary Prato
    Abstract:

    HIV-1 Protease inhibitors continue to play an important role in the treatment of HIV/AIDS, transforming this deadly ailment into a more manageable chronic infection. Over the years, intensive research has led to a variety of approved Protease inhibitors for the treatment of HIV/AIDS. In this review, we outline current drug design and medicinal chemistry efforts toward the development of next-generation Protease inhibitors beyond the currently approved drugs.

Irene T. Weber - One of the best experts on this subject based on the ideXlab platform.

  • structural studies of antiviral inhibitor with hiv 1 Protease bearing drug resistant substitutions of v32i i47v and v82i
    Biochemical and Biophysical Research Communications, 2019
    Co-Authors: Shrikant Pawar, Arun K Ghosh, Johnson Agniswamy, Y F Wang, Andres Wongsam, Robert W Harrison, Irene T. Weber
    Abstract:

    Abstract HIV-1 Protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 Protease with drug resistant mutations of V32I, I47V and V82I (PRTri) that model the inhibitor-binding site of HIV-2 Protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type Protease, however, the measured inhibition constants for PRTri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PRTri mutant in complex with inhibitor 1 at 1.5 A resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

  • Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies
    2018
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro Hattori, Hiroaki Mitsuya
    Abstract:

    We have designed, synthesized, and evaluated a new class of potent HIV-1 Protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 Protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 Protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored

  • Room Temperature Neutron Crystallography of Drug Resistant HIV‑1 Protease Uncovers Limitations of X‑ray Structural Analysis at 100 K
    2017
    Co-Authors: Oksana Gerlits, David A. Keen, Matthew P. Blakeley, John M. Louis, Irene T. Weber, Andrey Kovalevsky
    Abstract:

    HIV-1 Protease inhibitors are crucial for treatment of HIV-1/AIDS, but their effectiveness is thwarted by rapid emergence of drug resistance. To better understand binding of clinical inhibitors to resistant HIV-1 Protease, we used room-temperature joint X-ray/neutron (XN) crystallography to obtain an atomic-resolution structure of the Protease triple mutant (V32I/I47V/V82I) in complex with amprenavir. The XN structure reveals a D+ ion located midway between the inner Oδ1 oxygen atoms of the catalytic aspartic acid residues. Comparison of the current XN structure with our previous XN structure of the wild-type HIV-1 Protease-amprenavir complex suggests that the three mutations do not significantly alter the drug–enzyme interactions. This is in contrast to the observations in previous 100 K X-ray structures of these complexes that indicated loss of interactions by the drug with the triple mutant Protease. These findings, thus, uncover limitations of structural analysis of drug binding using X-ray structures obtained at 100 K

  • Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV‑1 Protease Inhibitors: Design, Synthesis, Protein X‑ray Structural Studies, and Biological Evaluation
    2016
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Manabu Aoki, Hironori Hayashi, Heather L. Osswald, Kristof Glauninger, Hiroaki Mitsuya
    Abstract:

    A series of potent HIV-1 Protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 Protease complexes revealed molecular insight into the inhibitor–protein interaction

  • highly potent hiv 1 Protease inhibitors with novel tricyclic p2 ligands design synthesis and protein ligand x ray studies
    Journal of Medicinal Chemistry, 2013
    Co-Authors: Arun K Ghosh, Irene T. Weber, Garth L Parham, Cuthbert D Martyr, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Yuanfang Wang, Masayuki Amano, Hiroaki Mitsuya
    Abstract:

    The design, synthesis, and biological evaluation of a series of HIV-1 Protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the Protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 Protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles.

Hiroaki Mitsuya - One of the best experts on this subject based on the ideXlab platform.

  • Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies
    2018
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro Hattori, Hiroaki Mitsuya
    Abstract:

    We have designed, synthesized, and evaluated a new class of potent HIV-1 Protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 Protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 Protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored

  • Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV‑1 Protease Inhibitors: Design, Synthesis, Protein X‑ray Structural Studies, and Biological Evaluation
    2016
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Manabu Aoki, Hironori Hayashi, Heather L. Osswald, Kristof Glauninger, Hiroaki Mitsuya
    Abstract:

    A series of potent HIV-1 Protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 Protease complexes revealed molecular insight into the inhibitor–protein interaction

  • highly potent hiv 1 Protease inhibitors with novel tricyclic p2 ligands design synthesis and protein ligand x ray studies
    Journal of Medicinal Chemistry, 2013
    Co-Authors: Arun K Ghosh, Irene T. Weber, Garth L Parham, Cuthbert D Martyr, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Yuanfang Wang, Masayuki Amano, Hiroaki Mitsuya
    Abstract:

    The design, synthesis, and biological evaluation of a series of HIV-1 Protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the Protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 Protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor’s potent antiviral activity and excellent resistance profiles.

  • 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
    Co-Authors: Arun K Ghosh, Irene T. Weber, Garth L Parham, Johnson Agniswamy, Yuanfang Wang, Masayuki Amano, Bruno D Chapsal, Melinda Steffey, Hiroaki Mitsuya
    Abstract:

    We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the 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 hydroxyethylsulfonamide 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.

  • 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
    Co-Authors: Aran K Ghosh, Irene T. Weber, Andrey Kovalevsky, Yuanfang Wang, Sandra Gemma, Abigail Baldridge, Yashiro Koh, Hiroaki Mitsuya
    Abstract:

    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 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.

Yuanfang Wang - One of the best experts on this subject based on the ideXlab platform.

  • Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies
    2018
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro Hattori, Hiroaki Mitsuya
    Abstract:

    We have designed, synthesized, and evaluated a new class of potent HIV-1 Protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 Protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 Protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored

  • Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis
    2018
    Co-Authors: Arun K Ghosh, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Masayuki Amano, Kanury V S Rao, Manabu Aoki, Satish Kovela, Margherita Brindisi, Yuanfang Wang
    Abstract:

    The design, synthesis, and biological evaluation of a new class of HIV-1 Protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand–backbone interactions in the Protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson–Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease revealed extensive interactions with the backbone atoms of HIV-1 Protease and provided molecular insight into the binding properties of these new inhibitors

  • design and development of highly potent hiv 1 Protease inhibitors with a crown like oxotricyclic core as the p2 ligand to combat multidrug resistant hiv variants
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Arun K Ghosh, Cuthbert D Martyr, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Yuanfang Wang, Kanury V S Rao, Manabu Aoki, Hironori Hayashi, Haydar Bulut
    Abstract:

    Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 Protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease revealed extensive interactions with the backbone atoms of HIV-1 Protease and provided molecular insight into the binding properties of these new inhibitors.

  • Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV‑1 Protease Inhibitors: Design, Synthesis, Protein X‑ray Structural Studies, and Biological Evaluation
    2016
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Manabu Aoki, Hironori Hayashi, Heather L. Osswald, Kristof Glauninger, Hiroaki Mitsuya
    Abstract:

    A series of potent HIV-1 Protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 Protease complexes revealed molecular insight into the inhibitor–protein interaction

  • design of hiv 1 Protease inhibitors with amino bis tetrahydrofuran derivatives as p2 ligands to enhance backbone binding interactions synthesis biological evaluation and protein ligand x ray studies
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Arun K Ghosh, Cuthbert D Martyr, Heather L Osswald, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Venkat Reddy Sheri, Luke A Kassekert, Shujing Chen, Manabu Aoki
    Abstract:

    Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 Protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 Protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 Protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.

Johnson Agniswamy - One of the best experts on this subject based on the ideXlab platform.

  • structural studies of antiviral inhibitor with hiv 1 Protease bearing drug resistant substitutions of v32i i47v and v82i
    Biochemical and Biophysical Research Communications, 2019
    Co-Authors: Shrikant Pawar, Arun K Ghosh, Johnson Agniswamy, Y F Wang, Andres Wongsam, Robert W Harrison, Irene T. Weber
    Abstract:

    Abstract HIV-1 Protease inhibitors are effective in HIV/AIDS therapy, although drug resistance is a severe problem. This study examines the effects of four investigational inhibitors against HIV-1 Protease with drug resistant mutations of V32I, I47V and V82I (PRTri) that model the inhibitor-binding site of HIV-2 Protease. These inhibitors contain diverse chemical modifications on the darunavir scaffold and form new interactions with wild type Protease, however, the measured inhibition constants for PRTri mutant range from 17 to 40 nM or significantly worse than picomolar values reported for wild type enzyme. The X-ray crystal structure of PRTri mutant in complex with inhibitor 1 at 1.5 A resolution shows minor changes in interactions with inhibitor compared with the corresponding wild type PR complex. Instead, the basic amine at P2 of inhibitor together with mutation V82I induces two alternate conformations for the side chain of Arg8 with new interactions with inhibitor and Leu10. Hence, inhibition is influenced by small coordinated changes in hydrophobic interactions.

  • Design and Synthesis of Potent HIV‑1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure–Activity Studies and Biological and X‑ray Structural Studies
    2018
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Hironori Hayashi, Jacqueline N. Williams, Hannah M. Simpson, Shin-ichiro Hattori, Hiroaki Mitsuya
    Abstract:

    We have designed, synthesized, and evaluated a new class of potent HIV-1 Protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 Protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme Ki of 40 pM and antiviral IC50 of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 Protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored

  • Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis
    2018
    Co-Authors: Arun K Ghosh, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Masayuki Amano, Kanury V S Rao, Manabu Aoki, Satish Kovela, Margherita Brindisi, Yuanfang Wang
    Abstract:

    The design, synthesis, and biological evaluation of a new class of HIV-1 Protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand–backbone interactions in the Protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson–Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease revealed extensive interactions with the backbone atoms of HIV-1 Protease and provided molecular insight into the binding properties of these new inhibitors

  • design and development of highly potent hiv 1 Protease inhibitors with a crown like oxotricyclic core as the p2 ligand to combat multidrug resistant hiv variants
    Journal of Medicinal Chemistry, 2017
    Co-Authors: Arun K Ghosh, Cuthbert D Martyr, Prasanth R Nyalapatla, Heather L Osswald, Johnson Agniswamy, Yuanfang Wang, Kanury V S Rao, Manabu Aoki, Hironori Hayashi, Haydar Bulut
    Abstract:

    Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 Protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6–5–5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels–Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 Protease revealed extensive interactions with the backbone atoms of HIV-1 Protease and provided molecular insight into the binding properties of these new inhibitors.

  • Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV‑1 Protease Inhibitors: Design, Synthesis, Protein X‑ray Structural Studies, and Biological Evaluation
    2016
    Co-Authors: Arun K Ghosh, Irene T. Weber, Johnson Agniswamy, Yuanfang Wang, Manabu Aoki, Hironori Hayashi, Heather L. Osswald, Kristof Glauninger, Hiroaki Mitsuya
    Abstract:

    A series of potent HIV-1 Protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 Protease complexes revealed molecular insight into the inhibitor–protein interaction