Small molecule kinase inhibitors (SMKIs) are of heightened interest in the field of drug research and development. There are 79 (as of July 2023) small molecule kinase inhibitors that have been approved by the FDA and hundreds of kinase inhibitor candidates in clinical trials that have shed light on the treatment of some major diseases. As an important strategy in drug design, computer-aided drug design (CADD) plays an indispensable role in the discovery of SMKIs. CADD methods such as docking, molecular dynamic, quantum mechanics/molecular mechanics, pharmacophore, virtual screening, and quantitative structure–activity relationship have been applied to the design and optimization of small molecule kinase inhibitors. In this review, we provide an overview of recent advances in CADD and SMKIs and the application of CADD in the discovery of SMKIs.

Esculetin is an important plant-derived natural product that has multiple bioactivities and applications. Phytophthora capsici is a notorious plant pathogen capable of infecting a broad range of hosts. In this study, we evaluated the antifungal activity of esculetin against P. capsici. The baseline sensitivity of P. capsici to esculetin was established using 108 isolates collected from various geographical regions in the Jiangsu and Shandong Provinces of China. The median effective concentration (EC₅₀) values for esculetin ranged from 2.08 to 16.46 μg/ml (mean, 6.87 ± 2.70 μg/ml) and were normally distributed. Furthermore, both zoospore production and germination were strongly inhibited by esculetin. Importantly, esculetin exhibited protective as well as curative activities against P. capsici on tomato and was capable of restricting the early infection of P. capsici on Nicotiana benthamiana. We found that the esculetin treatment led to cell membrane damage of P. capsici, as revealed by morphological observations and measurements of relative conductivity and malondialdehyde (MDA). Finally, our results also suggested that esculetin may adversely affect P. capsici by inhibiting its DNA and protein synthesis. These findings will contribute to the broader evaluation of the use of esculetin to control diseases caused by P. capsici and toward a better understanding of its mode of action as a potential fungicide.

Pathogenic plant oomycetes cause devastating damage to fruits and vegetables worldwide. Plant essential oils (EOs) are known to be promising candidates for the development of fungicides. In this study, we isolated twelve EOs from Tetradium ruticarpum, Tetradium daniellii, Tetradium fraxinifolium, Zanthoxylum armatum, Ruta graveolens, and Citrus medica leaves and fruits. We then investigated their chemical composition and antifungal activity against phytopathogenic oomycetes. Our results demonstrated that Z. armatum fruit essential oil (ZFO) in particular substantially inhibited the mycelial growth of Phytophthora capsici. Similarly, ZFO also strongly suppressed spore production and germination of P. capsici, and the application of ZFO significantly reduced disease symptoms caused by P. capsici in pepper. Furthermore, results from microscopic and biochemical studies indicated that ZFO damaged the ultrastructure and destroyed the membrane integrity of P. capsici, leading to the leakage of the cellular contents and ultimately causing cell death. It was concluded that ZFO could enhance the activities of defense-related enzymes in pepper fruits, which may also be responsible for the inhibition of phytophthora disease. Moreover, linalool and D-limonene were proven to be the primary effective components of ZFO. Our results collectively indicate that ZFO could be a potential candidate for the management of disease caused by P. capsici.

Benzylisoquinoline alkaloids (BIAs) are a prominent class of plant metabolites with significant pharmaceutical and industrial significance that have garnered substantial attention from researchers worldwide. BIAs exhibit several pharmacological activities and have been used extensively. Examples include analgesics such as morphine, tetrahydropalmatine, antimicrobials such as berberine, and antineoplastic agents including cepharanthine. Most BIAs are derived and isolated from medicinal plants; however, these plants are predominantly wild resources that are scarce. Their high environmental impact, slow growth rate, scarcity of resources, and expensive direct extraction costs pose a significant challenge. Certain BIAs are present in trace amounts in medicinal plants; moreover, they have complex chemical structures and unstable properties. Designing chemical synthesis routes and processes is challenging. Thus, a major obstacle in developing and utilizing these natural products in the pharmaceutical industry lies in their low abundance in nature. Consequently, the limited supply of these molecules fails to meet high research and market demands. In recent years, biosynthesis approaches have emerged as a novel and efficient method to obtain BIAs. In this review, recent progress in the field of enzymes related to the elucidation of biosynthetic pathways and the biosynthesis of BIAs are discussed, and future perspectives for designing viable strategies for their targeted manipulation are presented.

Two novel lathyrane-type diterpenoids, which possess atrans-gem-dimethylcyclopropane were obtained from seeds ofEuphorbia lathyris. TheEuphorbiafactor L_2bexhibited an inhibitory effect against U937 cell line with an IC₅₀value of 0.87 μM.