Methodology to calculate electronic chiroptical properties from time-dependent density functional theory (TDDFT) is outlined. Applications of TDDFT to computations of electronic circular dichroism, optical rotation, and optical rotatory dispersion are reviewed. Emphasis is put on publications from 2005 to 2010, but much of the older literature is also cited and discussed. The determination of the absolute configuration of chiral molecules by combined measurements and computations is an important application of TDDFT chiroptical methods and discussed in some detail. Raman optical activity (ROA) spectra are obtained from normal-mode derivatives of the optical rotation tensor and other linear response tensors. A few selected (ROA) benchmarks are reviewed.

Glu-167 of triosephosphate isomerase from Trypanosoma brucei brucei (TbbTIM) acts as the base to deprotonate substrate to form an enediolate phosphate trianion intermediate. We report that there is a large ~6 pK unit increase in the basicity of the carboxylate side chain of Glu-167 upon binding of the inhibitor phosphoglycolate trianion (I3−), an analog of the enediolate phosphate intermediate, from pKEH ≈ 4 for the protonated free enzyme EH to pKEHI ≈ 10 for the protonated enzyme-inhibitor complex EH•I3−. We propose that there is a similar increase in the basicity of this side chain when the physiological substrates are deprotonated by TbbTIM to form an enediolate phosphate trianion intermediate and that it makes an important contribution to the enzymatic rate acceleration. The affinity of wildtype TbbTIM for I3− increases 20,000-fold upon decreasing the pH from 9.3 to 4.9, because TbbTIM exists mainly in the basic form E over this pH range, while the inhibitor binds specifically to the rare protonated enzyme EH. This reflects the large increase in the basicity of the carboxylate side chain of Glu-167 upon binding of I3− to EH to give EH•I3−. The I172A mutation at TbbTIM results in an ~100-fold decrease in the affinity of TbbTIM for I3− at pH < 6, and an ~2 pK unit decrease in the basicity of the carboxylate side chain of Glu-167 at the EH•I3− complex, to pKEHI = 7.7. Therefore the hydrophobic side chain of Ile-172 plays a critical role in effecting the large increase in the basicity of the catalytic base upon the binding of substrate and/or inhibitors.

The optical rotation of natural amino acids becomes more positive when the medium is changed from approximately neutral to strongly acidic (Clough-Lutz-Jirgensons (CLJ) effect). In this work, it is shown by time-dependent density functional computations that the effect can be generalized to other α-substituted chiral carboxylic acids. The physical origin of the generalized CLJ effect is similar to that in amino acids, linking the absolute configuration directly to the sign of CLJ. For conformationally flexible molecules with small magnitudes of the optical rotation, the presence of a CLJ effect might aid the assignment of absolute configurations based on comparing experimental data with computed chiroptical responses.

Context: The antimicrobial resistant era requires advances in the approaches and technologies to find new treatments. The enhancement of the antimicrobial activity of commercially available drugs (CADs) by natural products (NPs) has successful mixtures (e.g., clavulanic acid and amoxicillin). Objective: To systematically review reports of synergistic effects of CADs and NPs against opportunistic microbial strains from 2010 to April 2016. Methods: The databases and search engines PubMed, Medline, Scifinder, Scopus, ScienceDirect, Scholar Google were systematically searched. Among the keywords utilized were: synergistic effects natural products and antibioitcs, botanicals and antibiotics bioassays, plant extracts interaction with antibioitics and antibiotic adjuvant bioassays. Only synergistic results were tabulated and analyzed according to CADs, NPs and strains. Results: A set of 76 studies that reported in vitro synergistic effects of CADs and NPs against gram−positive or gram−negative bacteria or fungi opportunistic strains was found. From the 60 reports on antibacterial adjuvants, the most frequent designs involved beta−lactamics or aminoglycosides against Methicillin Resistant Staphylococcus aureus. The assayed NPs encompassed extracts or fractions from 22 different species distributed worldwide (45% extracted with non−polar solvents) and 33 purified compounds (flavonoids, other polyphenols and alkaloids). Conclusions: NPs as potential drug hits for antimicrobial adjuvants had been found and should continue in the drug discovery pipeline. The field certainly would benefit of advances in purification technologies, especially for polar extracts and bioassay platforms.