Exploration of the Conformational Space of a Polymeric Material that Inhibits Human Immunodeficiency Virus

Abstract

Baertschi et al. (Antiviral Chem. Chemother. 1997, 8, 353-362) clarified the nature of a polymeric degradation product formed from the cephalosporin ceftazidime. Interest in the polymeric material arises from its ability to inhibit the RNase H and polymerase activities of HIV-1 reverse transcriptase (RT). To shed light on the structure of the polymeric material like that which forms from degradation of third-generation cephalosporins, we apply molecular modeling and other computational chemistry techniques. Aminothiazole methoxime (2-amino-4-thiazolyl-methoxyimino; ATMO) is the parent structure related to the isolated degradation product of ceftazidime. The MMFF94 force field and Monte Carlo multiple minimum method as implemented in MacroModel are used to generate low-energy conformers. We built up oligomeric models starting from the trimer to the 16-mer and performed distribution analyses on the dihedral angles from the Monte Carlo runs to analyze the three-dimensional shapes of the oligomers. Although the larger oligomers are too long for a complete search of conformational space, the low-energy conformers examined do not show secondary structure or repetitive conformations. Polymeric ATMO material may, therefore, exhibit only random coil conformations. Topological similarity of ATMO structures to other reported RT inhibitors is also examined.

Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists

“…Potency and rate of generation from ceftazidime led to a focus on compound Z. Fractionation by size exclusion chromatography (SEC) demonstrated broad high molecular weight of the activity (Figures 1D and 1E), consistent with the reported polymerization of a negatively charged R group degradant of ceftazidime (Baertschi et al, 1997; Ercanli and Boyd, 2006). Both cefixime and ceftazidime possess a negatively charged R group, while other cephalosporins do not, consistent with this group being required (Figure 1C).…”

“…Consequently, we sought insight from the chemical nature of Z for a directed approach to inhibitor development. A polymeric ceftazidime degradant has been reported to possess anti-HIV activity (Hobi et al, 2001) with a hypothetical structure containing repeating acidic subunits (Baertschi et al, 1997; Ercanli and Boyd, 2006). To explore the composition of Z, we purified active Z from aged ceftazidime by either size exclusion or anion exchange chromatography, followed by replicated elemental analysis.…”

New Class of Heterogeneous Helical Peptidomimetics

“…Maestro Macromodel was then used to carry out NOE-restrained molecular dynamics calculations (Tables S7 and S8). The 10 best structures were generated (Figure S8a) that display a good overlap on their backbones (rmsd = 1.08 ± 0.34 Å, Table S9).…”

“…This suggests that h1 may have a well-defined secondary folding structure. As such, Maestro Macromodel was used to carry out NOE-restrained molecular dynamics calculations (Tables S2 and S3). The 10 best structures were generated (Figure a), and they display a good overlap on their backbones (rmsd = 0.89 ± 0.15 Å, Table S4).…”

Sulfono‐γ‐AApeptides as a New Class of Nonnatural Helical Foldamer

“…The NMR solution structure was solved and is displayed in Figure 6. Schrödinger Macromodel20 was used to perform molecular dynamics calculations based upon the NOE constraints, which resulted in the ten best structures. As shown in Figure 6 b, the structures display very good overlap among backbone atoms (rmsd=(0.72±0.29) Å, Figure 6 b, and Table S3 in the Supporting Information).…”