Structure-activity studies of synthetic FKBP ligands as peptidyl-prolyl isomerase inhibitors

Holt, Dennis A.; Konialian‐Beck, A.; Oh, Hye-Ja; Yen, Hwa-Kwo; Rozamus, Leonard W.; Krog, A. J.; Erhard, Karl F.; Ortiz, Elizabeth; Levy, Mark A.; Brandt, Martín; Bossard, Mary J.; Luengo, Juan I.

doi:10.1016/s0960-894x(01)80135-9

Cited by 39 publications

(41 citation statements)

References 13 publications

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“…A reported derivative of the pipecolinyl moiety is a weak binding ligand (39). Although a specific tripeptide consistently appears among millions of candidates that bind streptavidin, this motif makes a relatively small number of interactions in the binding site of the protein (21).…”

Section: Concepts Of Lead Discoverymentioning

confidence: 99%

Unraveling principles of lead discovery: from unfrustrated energy landscapes to novel molecular anchors.

Rejto

Verkhivker

1996

Proc. Natl. Acad. Sci. U.S.A.

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The search for novel leads is a critical step in the drug discovery process. Computational approaches to identify new lead molecules have focused on discovering complete ligands by evaluating the binding affinity of a large number of candidates, a task of considerable complexity. A new computational method is introduced in this work based on the premise that the primary molecular recognition event in the protein binding site may be accomplished by small core fragments that serve as molecular anchors, providing a structurally stable platform that can be subsequently tailored into complete ligands. To fulfill its role, we show that an effective molecular anchor must meet both the thermodynamic requirement of relative energetic stability of a single binding mode and its consistent kinetic accessibility, which may be measured by the structural consensus of multiple docking simulations. From a large number of candidates, this technique is able to identify known core fragments responsible for primary recognition by the FK506 binding protein (FKBP-12), along with a diverse repertoire ofnovel molecular cores. By contrast, absolute energetic criteria for selecting molecular anchors are found to be promiscuous. A relationship between a minimum frustration principle of binding energy landscapes and receptor-specific molecular anchors in their role as "recognition nuclei" is established, thereby unraveling a mechanism of lead discovery and providing a practical route to receptor-biased computational combinatorial chemistry. Concepts of Lead DiscoveryUnderstanding the principles of molecular recognition is a long-standing problem in molecular biology (1, 2). Methods to discover novel lead molecules and assess their binding affinity and receptor specificity are of considerable utility in receptor structure-based drug design (3-7). Approaches that computationally screen data bases for complete inhibitors (8-15) are required to both assess the structure of the bound ligandprotein complex and reliably estimate the binding free energy. Each candidate is ranked on the basis of the best energetic orientation, evaluated by criteria such as packing density, electrostatic complementarity, molecular mechanics force field energy, and empirical solvation free energy corrections (8-11). These scoring functions, which are approximate for binding affinity, often are unable to distinguish between the structures of native and nonnative ligand-protein complexes. A detailed description of ligand-protein association involves a delicate balance between van der Waals and electrostatic interactions, solvation effects, and conformational entropy, resulting in a highly frustrated energy landscape of molecular recognition with many energetically similar but structurally different local minima, which makes reliable structure prediction difficult (16,17). Hence, even if a thermodynamically complete and accurate energy function suitable for rigorous predictions of binding affinity were available, it would not solve the equally important problem o...

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Section: Concepts Of Lead Discoverymentioning

confidence: 99%

Unraveling principles of lead discovery: from unfrustrated energy landscapes to novel molecular anchors.

Rejto

Verkhivker

1996

Proc. Natl. Acad. Sci. U.S.A.

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“…The design of synthetic inhibitors of FKBP12 has been an area of intense interest (Bierer et al, 1990;Hauske et al, 1992;Teague & Stocks, 1993;Wang et al, 1994;Yamashita et al, 1994;Luengo et al, 1994;Holt et al, 1994;Stocks, Birkinshaw & Teague, 1994;Goulet, Rupprecht, Sinclair, Wyvratt & Parsons, 1994). As part of our ongoing immunosuppressive program, we sought to probe the binding site of FKBP12 by identifying small-molecule inhibitors of this immunophilin with affinity equal to or greater than FK506.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protein for the immunosuppressant FK506

Armistead¹,

Badia²,

Deininger³

et al. 1995

Acta Cryst D

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We have synthesized a series of non-macrocyclic ligands to FKBP12 that are comparable in binding potency and peptidyl prolyl isomerase (PPIase) inhibition to FK506 itself. We have also solved the structure of one of these ligands in complex with FKBP12, and have compared that structure to the FK506-FKBP 12 complex. Consistent with the observed inhibitory equipotency of these compounds, we observe a strong similarity in the conformation of the two ligands in the region of the protein that mediates PPIase activity. Our compounds, however, are not immunosuppressive. In the FKBP12-FK506 complex, a significant portion of the FK506 ligand, its 'effector domain', projects beyond the envelope of the binding protein in a manner that is suggestive of a potential interaction with a second protein, the calcium-dependent phosphatase, calcineurin, whose inhibition by the FKBP 12-FK506 complex interrupts the T-cell activation events leading to immunosuppression. In contrast, our compounds bind within the surface envelope of FKBP12, and induce significant changes in the structure of the FKBP12 protein which may also affect calcineurin binding indirectly.

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“…In order to find novel inhibitors of Mip, two previously reported pipecoline ring containing inhibitors A and B with K i (app) of 10 nM and 0.23 µM, respectively, were used as lead structures. While structure A contained the keto amide moiety, in structure B this group was replaced by a sulfonamide anchor (Holt et al, 1993(Holt et al, , 1994. Molecular docking studies revealed that structure A fitted less well to Mip than to the human homolog FKBP12.…”

Section: Pipecolinic Acid Derivativesmentioning

confidence: 99%

FKBPs in bacterial infections

Ünal

Steinert

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Structure-activity studies of synthetic FKBP ligands as peptidyl-prolyl isomerase inhibitors

Cited by 39 publications

References 13 publications

Unraveling principles of lead discovery: from unfrustrated energy landscapes to novel molecular anchors.

Unraveling principles of lead discovery: from unfrustrated energy landscapes to novel molecular anchors.

Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protein for the immunosuppressant FK506

FKBPs in bacterial infections

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