Protein kinase CK2 type α (CK2α) inhibitors are expected to be a new anticancer drug and a treatment for nephritis. Virtual screening for CK2α inhibitors has been conducted and active compounds with various scaffolds have been obtained. Research on compound optimization is currently in progress for some of them with the aim of improving their activity. This process involves the combination of various computational chemistry methods and crystal analyses. In this review, case studies of structure-based compound designs that have efficiently improved the activity of screening hit compounds, including compounds with a thiadiazole ring and a purine scaffold, are introduced.

Owing to the increasing use of computers, computer-aided drug design (CADD) has become an essential component of drug discovery research. In structure-based drug design (SBDD), including inhibitor design and in silico screening of drug target molecules, concordance with wet experimental data is important to provide insights on unique perspectives derived from calculations. Fragment molecular orbital (FMO) method is a quantum chemical method that facilitates precise energy calculations. Fragmentation method makes it possible to apply the quantum chemical method to biological macromolecules for energy calculation based on the electron behavior. Furthermore, interaction energies calculated on a residue-by-residue basis via fragmentation aid in the analysis of interactions between the target and ligand molecule residues and molecular design. In this review, we outline the recent developments in SBDD and FMO methods and highlight the prospects of developing machine learning approaches for large computational data using the FMO method.

The use of computational methods in drug discovery research has increased substantially in recent years. Computational chemistry techniques, such as quantum chemical calculations and molecular dynamics simulations, continue to be widely used. In this review, we focused on drug discovery-related studies that employ fragment molecular orbital methods. Furthermore, we focused on inhibitor discovery, protein–protein interaction analysis, including antigen–antibody interaction analysis, and integration with molecular dynamics simulations.

Recently, remarkable progress has been achieved in artificial intelligence (AI), including machine learning. Various AI models have been proposed for drug discovery, including the design of small molecules, activity prediction, and three-dimensional (3D) structure prediction of proteins. AI consists of diverse elements, including information retrieval and machine learning, and can be used in a wide range of drug discovery scenarios. In this review, we focused on AI for small-molecule drug discovery with respect to molecular design, activity prediction, and prediction of the binding poses of compounds to target molecules. We also discussed the applications of AI in academic drug discovery.

A noise filter, which is usually attached to a detector for chromatography, was applied for the improvement of a signal-to-noise ratio (S/N) on a chromatogram. The objective of this paper is to elucidate the effect of noise filtering in an UV detector of ultra HPLC (UHPLC) on the statistical reliability of chemometrically evaluated repeatability by the function of mutual information (FUMI) theory. To examine the statistical reliability of chemometrically evaluated repeatability in the UHPLC system associated with noise filtering, the standard deviation (SD) values of the area in baseline fluctuations with peak region k (s(k)) were obtained from six chromatograms with noise filtering. Further, the average of s(k) values (σ̂) was calculated from the s(k) values (n = 6) to be alternatively applied as the population SD. All s(k)/σ̂ values were within the 95% confidence intervals (CIs) at the freedom degree of 50, indicating the chemometrically estimated relative SD (RSD) of a peak area and RSD by repeated measurements of at least 50 times had equivalent reliability.

Protein-based enzymes are among the most efficient catalysts on our planet. A common feature of protein enzymes is that all catalytic amino acids occupy a limited, narrow space and face each other. In this study, we created a theoretical novel biomimetic molecule containing different multiple catalytic peptides. Although single peptides are far less catalytically efficient than protein enzymes, Octopus-arms-mimicking biomolecules containing eight different peptides (Octopuzymes) can efficiently catalyze organic reactions. Since structural information for extant protein enzymes, predicted enzymes based on genome data, and artificially designed enzymes is available for designing Octopuzymes, they could in theory mimic all protein enzyme reactions on our planet. Moreover, besides L-amino acids, peptides can contain D-amino acids, non-natural amino acids, chemically modified amino acids, nucleotides, vitamins, and manmade catalysts, leading to a huge expansion of catalytic space compared with extant protein enzymes. Once a reaction catalyzed by an Octopuzyme is defined, it could be rapidly evolvable via multiple amino acid substitutions on the eight peptides of Octopuzymes.

Twisted intramolecular charge transfer (TICT) is a phenomenon involving intramolecular charge transfer together with intramolecular rotation upon photoexcitation, and in general this excited state of fluorescent dyes undergoes non-radiative decay (producing no fluorescence). We recently discovered that the magnitude of TICT in rhodamine derivatives could be regulated by altering the size of the substituents on the xanthene moiety, generating differing degrees of intramolecular steric repulsion. To further illustrate the usefulness and generality of this strategy, we describe here an application of quinone methide chemistry, which is widely used as a fluorescence off/on switching reaction for fluorescence probes detecting enzymatic activity, to construct a steric repulsion-induced (sr)-TICT-based fluorescence probe targeting nitroreductase (NTR) activity. The developed probe was almost non-fluorescent in phosphate-buffered saline (PBS) due to strong induction of the TICT state. On the other hand, when the probe was incubated with NTR and nicotinamide adenine dinucleotide (NADH), a large fluorescence increase was observed over time. We confirmed that the enzymatic reaction proceeded as expected, i.e., the nitro group of the probe was reduced to the corresponding amino group, followed by spontaneous elimination of iminoquinone methide. These results suggest that our simple design strategy based on the sr-TICT mechanism, i.e., controlling intramolecular steric repulsion, would be applicable to the development of fluorescence probes for a variety of enzymes.

The triboelectric properties of active pharmaceutical ingredients (APIs) contribute to problems during the manufacturing of pharmaceuticals. However, the triboelectric properties of APIs have not been comprehensively characterized. In this study, the effect of salt formulation on the triboelectric properties of APIs was investigated. The triboelectric properties of three groups of amines, namely tertiary amines, purine bases, and amino acids, and their hydrochlorides were evaluated using a suction-type Faraday cage meter. Most of the hydrochloride salts exhibited more negative charges than the corresponding free bases, and the degree by which the triboelectric property changed upon hydrochlorination depended on the structural groups of the compounds. In the case of tertiary amines, the change in the zero-charge margin upon hydrochlorination was negatively correlated with the zero-charge margin of the free base. In contrast, hydrochlorination of the amino acids led to a significant change in the zero-charge margin. In most cases, salt formation also affected the triboelectric properties of API powders. Controlling the triboelectric properties of APIs solves various problems caused by the electrification of raw material powders and granules during the production of pharmaceuticals, thereby increasing the quality of produced pharmaceuticals.

Surugamides are a group of non-ribosomal peptides produced by Streptomyces spp. Several derivatives possess acyl groups, which are proposed to be attached to a lysine side chain after backbone-macrocyclization during biosynthesis. To date, five different acyl groups have been identified in nature, yet their impacts on biological activity remain underexplored. Here we synthesized surugamide B derivatives with varied acyl moieties. Biological evaluations revealed that larger hydrophobic acyl groups on lysine ε-NH₂ enhance cytotoxicity.

Mid-sized cyclic peptides are a promising modality for modern drug discovery. Their larger interaction area coupled with an appropriate secondary structure is more suitable than small molecules for binding to the target protein. In this study, we conducted a structure derivatization of an immunoglobulin G (IgG)-binding peptide (15-IgBP), a β-hairpin-like cyclic peptide with a twisted β-strand and assessed the effect of the secondary structure on IgG-binding activity using circular dichroism (CD) spectra analysis. As a result, derivatization at the Ala5 and Gly9 positions affected the secondary structure of 15-IgBP, in particular the appearance of a small positive peak in the 220–240 nm region characteristic of 15-IgBP in the CD spectrum. Maintaining this peak at a moderate level may be important for the expression of IgG binding activity. We found the small methyl group at Ala5 to be crucial for retaining the preferred secondary structure; we also found Gly9 could be replaced by D-amino acids. By integrating these findings with previous results of the structure–activity relationship, we obtained four potent affinity peptides for IgG binding (K_d = 4.24–5.85 nM). Furthermore, we found the Gly9 position can be substituted for D-Lys. This is a new potential site for attaching functional units for conjugation with IgG for the preparation of homogeneous antibody–drug conjugates.

Monoammonium glycyrrhizic acid (MAG), a glycyrrhizic acid monoammonium salt, is a naturally derived low-molecular-weight gelling agent with surface-active properties. It has the capacity to individually facilitate the preparation of gel-solubilized drugs. As MAG is an anionic surfactant with carboxyl groups, the addition of counterions may affect micelle formation and gelation. In this study, the solubilization and gelling properties of MAG were investigated following the addition of metal salts (NaCl and KCl). The addition of metal salts resulted in a decrease in the critical micelle concentration and an increase in gel hardness. Supersaturation of curcumin (CUR) was maintained by the addition of metal salts because of increased micelle number and viscosity. When the gel hardness was compared between formulations with and without CUR, a significant reduction in hardness was observed with the solubilization of CUR. The addition of KCl prevented the decrease in the hardness of gels containing CUR compared to the addition of NaCl. Put together, the addition of metal salts had a noteworthy impact on micelle and gel formation of MAG. In particular, the addition of KCl was more effective in the preparation of gel-solubilized CUR.