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HIV-1 protease inhibitors are one of the two widely used therapeutic agents for the treatment of HIV-infected patients. The investigation of HIV-1 protease−inhibitor interactions can provide further insight for developing new compounds that are still required due to the growing problem of drug resistance. To this end, a combined QM/MM approach was used to determine electrostatic and polarization interactions on three high affinity inhibitors, nelfinavir, mozenavir, and tipranavir. The present computational results show that explicit treatment of the polarization effect is particularly important since it can contribute as much as one-third of the total electrostatic interaction energy. Further, an amino acid decomposition analysis was applied to determine contributions of individual residues to the enzyme−inhibitor interactions. It was found that the 4-hydroxy-dihydropyrone substructure of tipranavir is especially suited for extended charge delocalization by interacting with the catalytic aspartates and isoleucines of the HIV-1 protease. The calculated electron density difference maps reaffirm and provide a means of visualizing these results.

The dopamine D3 receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D3 versus D2 receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with markedly improved affinity and selectivity. Molecular modeling studies supported the structural development. Pharmacophore models for dopamine D2 and D3 receptor ligands were developed from their potentially bioactive conformation and were compared in order to get insight into molecular properties of importance for D2/D3 receptor selectivity. For the 72 compounds presented here, an extended and more linear conformation in the aliphatic or aryl spacers turned out to be crucial for dopamine D3 receptor selectivity. Structural diversity in the aryl moiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolar D3 receptor affinity, which was optimized with more rigid aryl acrylamide derivatives. Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide) displayed a most promising pharmacological profile (Ki (hD3) = 0.5 nM; Ki (hD2L) = 76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novel radioligand as a pharmacological tool for various D3 receptor-related in vitro and in vivo investigation.

Starting from 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), we performed the design, synthesis, and the structure−activity relationship studies of a series of 2,3-diaryl-1,3-thiazolidin-4-ones. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations with minimal cytotoxicity, thereby acting as nonnucleoside HIV-1 RT inhibitors (NNRTIs). Computational studies were used to delineate the ligand-RT interactions and to probe the binding of the ligands to HIV-1 RT.

A three-dimensional molecular model of the transmembrane domain of the κ-opioid receptor in a phospholipid bilayer is presented. The endogenous ligand, dynorphin A (1), and synthetic ligands, benzomorphan-based compounds (2a, 2b) (Figure 1), are docked into the model. We report the results of a 500 ps molecular dynamics simulation of these protein−ligand complexes in a simplified bilayer of 97 molecules of the lipid dipalmitoylphosphatidylcholine and 26 water molecules per lipid. The simulations explore the stability and conformational dynamics of the model in a phospholipid bilayer; we also investigate the interactions of the protein with its ligands. Molecular simulation of the receptor−ligand complexes, endogenous and synthetic, has confirmed the existence of different binding domains for peptide and non-peptide ligands. Similarities are found in the dynamics and binding mode of all conformations of the synthetic ligands studied. The protonated hydrogen of the benzomorphan is always involved in an H-bond with Asp138, and other potentially stabilizing receptor−ligand interactions found involve the hydroxyl substituent on the benzomorphan, which may form an H-bond with Tyr139 or Gly190 according to the different molecules. The ester group of 2a may therefore form an H-bond with Ile316, while the carbonyl group of 2b forms an H-bond with Gln115 and Tyr312. The remaining part of the ligand is located in the extracellular portion of the pocket. It is surrounded by hydrophobic residues in the transmembrane region (TM), and it interacts with different sets of residues. The results obtained are in general agreement with site-directed mutagenesis data that have highlighted the importance of all TM regions for synthetic-ligand affinity with the κ-opioid receptor.

In order to study the conformational behavior of poly(l-glutamic acid) (PGA) at the air/water interface under the influence of compression and expansion forces, PGA was spread on an aqueous acidic subphase and studied by the Langmuir technique. Several distinct regions of the first compression surface pressure/area (π/A) isotherm could be identified by the starting and inflection point of the isotherm and by the beginning and the center of the pseudoplateau. The interpretation of the characteristic shape of the π/A isotherms in the sense of a side-by-side and an interdigitated organization of helical rods is strongly supported by molecular modeling calculations. But the helical surface layer is sensitive to repeated expansion and compression. A well-defined and reaction-kinetic demonstrable change occurs. The reasons for this transformation are discussed. Solidified regions are forming in the layer. Finally, after several compression/expansion cycles a more rigid monolayer results than that formed by helical rods exclusively. These monolayer ruptures on expansion and clods of PGA molecules were observed using Brewster angle microscopy and ellipsometry.