Herbal products are widely used in cancer patients via co-administration with chemotherapy. Previous studies have demonstrated that pharmacokinetic interactions between herbs and anticancer drugs exist due to inhibition of drug-metabolizing enzymes, particularly cytochrome P450s (CYPs). The aim of this study was to determine the inhibitory effects of Andrographis paniculata, Curcuma zedoaria, Ganoderma lucidum, Murdannia loriformis and Ventilago denticulata extracts on the metabolism of gefitinib, lapatinib and sorafenib. The activities of CYP3A in human liver microsome on the metabolism of gefitinib, lapatinib and sorafenib in the absence and presence of Thai herbal extracts were assayed using high-performance liquid chromatography analysis. Curcuma zedoaria extract potently inhibited CYP3A-mediated lapatinib and sorafenib metabolism with IC50 values of 4.18 ± 3.20 and 7.59 ± 1.23 μg/mL, respectively, while the metabolism of gefitinib was strongly inhibited by Murdannia loriformis and Ventilago denticulata extracts with IC50 values of 7.53 ± 2.87 and 7.06 ± 1.23 μg/mL, respectively. Andrographis paniculata and Ganoderma lucidum extracts had less effect on the metabolism of the tested anticancers (IC50 values >10 μg/mL). In addition, kinetic analysis of the ability of Curcuma zedoaria extract to inhibit CYP3A-mediated metabolism of anticancer drugs was best described by the noncompetitive and competitive inhibition models with Ki values of 20.08 and 11.55 μg/mL for the metabolism of gefitinib and sorafenib, respectively. The present study demonstrated that there were potential pharmacokinetic interactions between tyrosine kinase inhibitors and herbal extracts.

Currently, the development of selective fluorescent probes toward targeted enzymes is still a great challenge, due to the existence of numerous isoenzymes that share similar catalytic capacity. Herein, a double-filtering strategy was established to effectively develop isoenzyme-specific fluorescent probe(s) for cytochrome P450 (CYP) which are key enzymes involving in metabolism of endogenous substances and drugs. In the first-stage of our filtering approach, near-infrared (NIR) fluorophores with alkoxyl group were prepared for the screening of CYP-activated fluorescent substrates using a CYPs-dependent incubation system. In the second stage of our filtering approach, these candidates were further screened using reverse protein-ligand docking to effectively determine CYP isoenzyme-specific probe(s). Using our double-filtering approach, probes S9 and S10 were successfully developed for the real-time and selective detection of CYP2C9 and CYP2J2, respectively, to facilitate high-throughput screening and assessment of CYP2C9-mediated clinical drug interaction risks and CYP2J2-associated disease diagnosis. These observations suggest that our strategy could be used to develop the isoform-specific probes for CYPs.

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, we replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (10, 19, 20 and 26) with markedly improved metabolic stability. Compared to PF74, analog 20 exhibited similar submicromolar potency, and much longer (51-fold) half-life in human liver microsomes (HLMs). Molecular docking corroborated that 20 binds to the PF74 binding site, and revealed distinct binding interactions conferred by the benzamide moiety. Collectively, our data support compound 20 as a promising antiviral lead.

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding \"molecular obesity\". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.