18 research outputs found
Homologous ligands accommodated by discrete conformations of a buried cavity
Conformational change in protein-ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design
Sulfonamido-substituted boronic acids as β-lactamase inhibitors for treatment of antibiotic-resistant bacterial infections
Disclosed herein inter alia are Boron containing compounds and methods for treating infections related to antibiotic resistant microorganisms
Homologous ligands accommodated by discrete conformations of a buried cavity
Conformational change in protein–ligand complexes is widely modeled, but the protein accommodation expected on binding a congeneric series of ligands has received less attention. Given their use in medicinal chemistry, there are surprisingly few substantial series of congeneric ligand complexes in the Protein Data Bank (PDB). Here we determine the structures of eight alkyl benzenes, in single-methylene increases from benzene to n-hexylbenzene, bound to an enclosed cavity in T4 lysozyme. The volume of the apo cavity suffices to accommodate benzene but, even with toluene, larger cavity conformations become observable in the electron density, and over the series two other major conformations are observed. These involve discrete changes in main-chain conformation, expanding the site; few continuous changes in the site are observed. In most structures, two discrete protein conformations are observed simultaneously, and energetic considerations suggest that these conformations are low in energy relative to the ground state. An analysis of 121 lysozyme cavity structures in the PDB finds that these three conformations dominate the previously determined structures, largely modeled in a single conformation. An investigation of the few congeneric series in the PDB suggests that discrete changes are common adaptations to a series of growing ligands. The discrete, but relatively few, conformational states observed here, and their energetic accessibility, may have implications for anticipating protein conformational change in ligand design
Fragment-guided design of subnanomolar beta-lactamase inhibitors active in vivo
International audienceFragment-based design was used to guide derivatization of a lead series of beta-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K-i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with beta-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime: 5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome beta-lactamase-based resistance, a key clinical challenge
Development and binding mode assessment of N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-D-glutamic acid (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells.
N-[4-[2-Propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-d-glutamic acid 1 (BGC 945, now known as ONX 0801), is a small molecule thymidylate synthase (TS) inhibitor discovered at the Institute of Cancer Research in London. It is licensed by Onyx Pharmaceuticals and is in phase 1 clinical studies. It is a novel antifolate drug resembling TS inhibitors plevitrexed and raltitrexed that combines enzymatic inhibition of thymidylate synthase with α-folate receptor-mediated targeting of tumor cells. Thus, it has potential for efficacy with lower toxicity due to selective intracellular accumulation through α-folate receptor (α-FR) transport. The α-FR, a cell-surface receptor glycoprotein, which is overexpressed mainly in ovarian and lung cancer tumors, has an affinity for 1 similar to that for its natural ligand, folic acid. This study describes a novel synthesis of 1, an X-ray crystal structure of its complex with Escherichia coli TS and 2'-deoxyuridine-5'-monophosphate, and a model for a similar complex with human TS
Design, Synthesis, Crystal Structures, and Antimicrobial Activity of Sulfonamide Boronic Acids as β-Lactamase Inhibitors
Increasing Chemical Space Coverage by Combining Empirical and Computational Fragment Screens
Most libraries for fragment-based
drug discovery are restricted
to 1,000–10,000 compounds, but over 500,000 fragments are commercially
available and potentially accessible by virtual screening. Whether
this larger set would increase chemotype coverage, and whether a computational
screen can pragmatically prioritize them, is debated. To investigate
this question, a 1281-fragment library was screened by nuclear magnetic
resonance (NMR) against AmpC β-lactamase, and hits were confirmed
by surface plasmon resonance (SPR). Nine hits with novel chemotypes
were confirmed biochemically with <i>K</i><sub>I</sub> values
from 0.2 to low mM. We also computationally docked 290,000 purchasable
fragments with chemotypes unrepresented in the empirical library,
finding 10 that had <i>K</i><sub>I</sub> values from 0.03
to low mM. Though less novel than those discovered by NMR, the docking-derived
fragments filled chemotype holes from the empirical library. Crystal
structures of nine of the fragments in complex with AmpC β-lactamase
revealed new binding sites and explained the relatively high affinity
of the docking-derived fragments. The existence of chemotype holes
is likely a general feature of fragment libraries, as calculation
suggests that to represent the fragment substructures of even known
biogenic molecules would demand a library of minimally over 32,000
fragments. Combining computational and empirical fragment screens
enables the discovery of unexpected chemotypes, here by the NMR screen,
while capturing chemotypes missing from the empirical library and
tailored to the target, with little extra cost in resources