Abstract Ab initio and semiempiridal (AM1) molecular orbital theory has been used to model the cleavage of formamide at the active site of carboxypeptidase A. The model active site consists of a zinc dication coordinated to two imidazoles, an acetate, a water with a hydrogen‐bonded formate, and a formamide molecule as model substrate. AM1 has been compared with ab initio theory for the coordination of water and formamide to Zn ++ and found to give excellent energetic results. The course of the amide cleavage was therefore calculated with AM1. The first step of the reaction is the dissociation of the zinc‐coordinated water to give an active ZnOH + species. The remote formate acts as proton acceptor. This process has an activation energy of only 4.6 kcal mol −1 . The next and rate‐determining step is the concerted addition of the ZnOH + moiety to the formamide CO bond. The ZnO distance in the transition state is more than 3 Å. In four further steps, the amide nitrogen is protonated and the CN bond cleaved. The net activation energy for the entire process is 15.5 kcal mol −1 relative to the active site model and 19.6 kcal mol −1 relative to the most stable point on the calculated reaction profile.
SATIS (simple atom type information system) is a protocol for the definition and automatic assignment of atom types and the classification of atoms according to their covalent connectivity. Its distinctive feature is that no bond type information is involved. Rather, the classification of each atom is based on a connectivity code describing the atom and its covalent partners. It is particularly useful when handling coordinate-based molecular representations with no bond order information, such as the PDB format. We survey the occurrence of the various connectivity codes in the 20 common amino acid residues in a sample of 304 different moieties from PDB protein−ligand complexes and also in a pseudo-random sample of 309 organic molecules from the CSD. We illustrate how connectivity codes can be grouped together to define atom types. We expect SATIS to be applicable to the derivation of atom types for statistical potentials, to the analysis of atomic interactions in structural databases, to studies of molecular similarity, and to the screening of virtual libraries in drug design.
A systematic thermodynamic analysis of benzene sulfonamide derivatives binding to carbonic anhydrase revealed a unique change in enthalpy for one of the compounds investigated. Subsequent X-ray analysis showed a different binding mode for this compound and further optimization led to a high-affinity, enthalpy-driven compound, emphasizing the importance of thermodynamic profiling. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Fragment-based drug discovery has proved to be a very useful approach particularly in the hit-to-lead process, providing a complementary tool to traditional high-throughput screening. Although often synonymous with fragment screening, fragment-based drug discovery is a far wider area covering high-throughput screening, fragment screening and virtual screening efforts. The unifying feature of fragment-based drug discovery is the low molecular weight of the hit rather than the approach it originates from. Over the last ten years, fragment-based drug discovery has provided in excess of 50 examples of small molecule hits that have been successfully advanced to leads and therefore resulted in useful substrate for drug discovery programs. To our knowledge, there are currently no marketed drugs that can be attributed to these efforts. However, due to the time scales of drug discovery and development it is likely that over the next few years the number of such examples will increase significantly.
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
This chapter focuses on attrition of candidate drugs, which have already overcome many significant hurdles, including safety studies in healthy volunteers, and which have, as a result of these, been considered sufficiently safe to progress further into clinical studies in patients particularly with the goal of establishing efficacy. It addresses the question if more could be done to take attrition in phase II rather than phase III or beyond. The chapter analyzes some of the specific case histories in order to identify some common features that could lead to valuable conclusions that would provide a way forward. The case histories include that of torcetrapib, dalcetrapib, onartuzumab, bapineuzumab, gantenerumab, solanezumab, pomaglumetad methionil, dimebon, BMS-986094, and many more. Where issues relate to a particular mechanism of action (mechanism associated toxicity, or lack of efficacy of mechanism), then failure of the entire cohorts of compounds from different companies are also not unexpected.
Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr–inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.
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