Zhe Wang

4‐Amino‐2,4‐pentadienoate‐containing cyclolipodepsipeptides (APD‐CLDs) represent a structurally distinctive family of natural products known for their selective activity against hypoxic cancer cells. To explore the structural diversity of APD‐CLDs, we have identified and prioritized cryptic APD‐CLD biosynthetic gene clusters (BGCs) for compound discovery. Using a combination of genetic and chemical methods, we successfully activated three dormant BGCs, leading to the discovery of 12 new APD‐CLDs. These newly discovered metabolites significantly expanded the diversity of the APD‐CLD family, with chloromalamides and arabimalamides representing the first halogenated and glycosylated members, respectively. Unexpectedly, chloromalamides and arabimalamides exhibited potent antiplasmodial activity, with IC ₅₀ values in the 25–161 nM range against drug‐sensitive and multidrug‐resistant Plasmodium falciparum strains. Phenotypic studies revealed arabimalamide B halted parasite development during the asexual blood stage life cycle, resulting in enlarged digestive vacuoles, dispersed hemozoin, and ultimately reduced reinvasion efficiency. These phenotypes are reminiscent of the effect of chloroquine and other 4‐aminoquinoline drugs, suggesting that arabimalamides may disrupt the parasite's heme detoxification mechanism. Biosynthetic studies identified key scaffold‐forming and modifying enzymes, including a rare membrane glycosyltransferase in arabimalamide biosynthesis. Together, these findings unveil APD‐CLDs as new antimalarial lead scaffolds and set the stage for structural diversification and optimization.

ent-Kaurane diterpenoids (ent-KTs) represent a structurally diverse class of natural products renowned for their antitumor and anti-inflammatory bioactivities. The C-14 hydroxyl modification is crucial for enhancing their potency; however, introducing this functional group remains a considerable challenge. Here, we present a computational heme-guided site-specific (CHS) strategy to identify three bacterial P450s (CYP260A1, CYP105N1, and CYP154C5) for C-14 hydroxylation. Further computationally guided enzyme engineering and redox partner screening identify the CYP260A1 L162V variant paired with CamA/CamB, achieving a 52-fold increase in production titer and a yield of 84.2 mg/L of (14R,16R)-ent-kauran-14,16-diol (2) in Escherichia coli. Substrate scope test reveals functional groups affecting reactivity. Structure-activity relationship studies demonstrate the synergistic effect between the C-14 hydroxyl and C15–C16 Michael acceptor, resulting in a potent derivative (27) with strong cytotoxicity (IC₅₀^HCT116 = 1.4 μM). This study demonstrates a framework combining CHS-guided P450 discovery and computational enzyme engineering to advance ent-KT modifications.

The identification of drug targets remains one of the most critical challenges in pharmaceutical research. The rapid progress of artificial intelligence (AI) is significantly advancing this landscape by enabling more efficient and accurate drug‐target interaction prediction. AI‐driven approaches can integrate and analyze massive biomedical datasets, elucidating complex signaling networks and providing systematic insights into drug mechanisms of action. These developments have greatly accelerated virtual screening, binding affinity estimation, and target identification. However, despite these advancements, key challenges persist, such as ensuring the precision of predictions and overcoming the barriers to integrating AI tools with drug target discovery. This review provides a comprehensive overview of recent public databases, advanced computational methods, and user‐friendly AI tools, highlighting both their potential and challenges. It also offers practical guidance for researchers without computational expertise, illustrating how these technologies can be effectively incorporated into current research workflows to advance drug target discovery and ultimately accelerate the development of novel therapeutic drugs.

Investigation of the secondary metabolites from the endophytic fungus Talaromyces primulinus WZ‐883, derived from the leaf of fresh Pseudostellaria heterophylla , led to the isolation of one new meroterpenoid, talapenoid A ( 1 ), and one new isocoumarin, talaromarin A ( 5 ), along with eight known compounds chrodrimanin B ( 2 ), chrodrimanin E ( 3 ), carnemycin B ( 4 ), aspergillumarin A ( 6 ), aspergillumarin B ( 7 ), 4‐hydroxy‐2,2‐dimethyl‐3,4‐dihydrochromene‐6‐carboxylic acid ( 8 ), penicichrysogene B ( 9 ), and 1‐naphthalenecarboxylic acid ( 10 ). Their structures were primarily determined through extensive spectroscopic analyses. The configurations were assigned using ROESY spectra, ECD, and NMR calculations, as well as x‐ray single crystal diffraction. Among them, compound 1 is an uncommon meroterpenoid featuring a 5/6/6/6‐pentacyclic α‐pyrone skeleton. All isolated compounds were evaluated for their inhibitory effects on pathogenic bacteria. Compounds 1 – 4 and 9 exhibited selective antibacterial activity against methicillin‐resistant Staphylococcus aureus (MRSA), S. aureus , Enterococcus faecalis , and Escherichia coli , but showed no significant activity against Shigella sonnei and Klebsiella pneumoniae .

Thirty highly oxidized hemiketal-containing polyketides, including 10 new ones (1-10) and 20 known analogues (11-30), were obtained from the endophytic fungus Trichoderma koningiopsis WZ-196 with the OSMAC strategy in combination with molecular network analysis. Their structures were elucidated through comprehensive spectroscopic analysis, together with NMR and ECD calculations. The phytotoxic activities of all compounds were evaluated using Arabidopsis thaliana (dicotyledonous) and Oryza sativa (monocotyledonous) as model systems. The results showed that most compounds exhibited significant inhibitory effects on seedling growth. Notably, compound 9 demonstrated the strongest phytotoxic activity against A. thaliana with an IC₅₀ value of 8.09 μM, while 24 markedly suppressed the growth of O. sativa with an IC₅₀ value of 9.42 μM, outperforming the commercial herbicide glyphosate under identical experimental conditions. These findings highlight the potential of hemiketal-containing polyketides derived from endophytic fungi as promising candidates for developing novel bioherbicides.