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.

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.

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.