Journal of Medicinal Chemistry最新文献

Cholesterol is structurally distinct from other lipids, which confers it with singular roles in membrane organization and protein function. As a signaling molecule, cholesterol engages in discrete interactions with transmembrane, peripheral, and certain soluble proteins to control cellular responses. Accordingly, the cholesterol–protein interface is central to cholesterol-related diseases and is an essential consideration in drug design. However, cholesterol’s hydrophobic, un-drug-like nature presents a unique challenge to traditional in silico analyses. In this Perspective, we survey a collection of tools designed to predict and evaluate cholesterol binding sites in proteins, including classical sequence motifs, molecular docking, template-based strategies, molecular dynamics simulations, and recent artificial intelligence approaches. We then comment on contemporary tools to evaluate ligand–protein interactions, their applicability to cholesterol, and the yet-untapped potential of cholesterol–protein interactions in human health and disease.

Mitochondrial uncouplers are small molecule protonophores that act to dissipate the proton motive force independent of adenosine triphosphate (ATP) synthase. Mitochondrial uncouplers such as BAM15 increase respiration and energy expenditure and have potential in treating a variety of metabolic diseases. In this study, we disclose the structure–activity relationship profile of 6-substituted [1,2,5]oxadiazolo[3,4-b]pyridin-7-ol derivatives of BAM15. Utilizing an oxygen consumption rate assay as a measure of increased cellular respiration, SHO1122147 (7m) displayed an EC₅₀ of 3.6 μM in L6 myoblasts. Pharmacokinetic studies indicated a half-life of 2 h, C_max of 35 μM, and no observed adverse effects at 1,000 mg kg^–1 dose in mice. In a Gubra-Amylin (GAN) mouse model of MASH, SHO1122147 was efficacious in decreasing body weight and liver triglyceride levels at 200 mg kg^–1 day^–1 without changes in body temperature. These findings indicate the potential of utilizing novel [1,2,5]oxadiazolo[3,4-b]pyridin-7-ol mitochondrial uncouplers for treatment of fatty liver disease and obesity.

The incorporation of silicon bioisosteres into pharmacological structures has been used as a strategy to improve the therapeutic potential of drugs. However, no secosteroidal silicon-containing VDR ligands have been developed. Here we report the design, synthesis, and biological activity of six analogues of the natural hormone 1,25-dihydroxyvitamin D3 (1,25D₃), which incorporate a silicon atom as a side chain-C25 isostere. The analogues were synthesized by the Wittig–Horner approach starting from Inhoffen-Lythgoe diol. The crystal structures of the complexes formed by the sila-analogues with the ligand binding domain of VDR revealed additional interactions of the sila-containing side chains that stabilize the VDR active conformation. These sila-analogues show similar VDR binding and transcriptional activity in comparison with the natural hormone 1,25D₃, but with significantly less hypercalcemic activity. The new analogues, when combined with chemotherapy, significantly decrease cell proliferation.

This work introduces a novel Pt(II) based prodrug TTFA-Platin that integrates a β-diketonate ligand TTFA with a platinum scaffold to structurally resemble carboplatin and offers intermediate kinetic lability between cisplatin and carboplatin, striking a balance between therapeutic efficacy and safety. A comprehensive stability and speciation study was conducted in various biological media, mapping the therapeutic effects of TTFA-Platin. A control molecule, TMK-Platin, was synthesized to further validate the structural-stability relationship, which displayed poor activatable features in biological systems. In vitro studies against a panel of cancer cell lines revealed that TTFA-Platin exhibited significantly higher potency compared to TMK-Platin. In vivo studies revealed that TTFA-Platin exhibited significantly lower toxicity than the reference platinum compounds. Thus, leveraging ligands that fine-tune kinetic lability and offer therapeutic benefits can help develop more effective and safer cancer treatments, addressing the limitations of existing therapies.

Guided by the mode of action of 13, our previously discovered RORγt inverse agonist, we conducted five rounds of design syntheses and structure–activity relationship (SAR) studies, ultimately identifying RORγt inverse agonist 5a, which exhibited superior in vitro activity compared to 13. Besides, 5a showed promising therapeutic effects in alleviating psoriasis in mice by intraperitoneal injection. Due to the high lipophilicity and in vitro pharmacokinetic properties of 5a, it was formulated into an ointment, which enabled effective skin retention and mitigated systemic side effects. The ointment of 5a was assessed in the mouse model, where it demonstrated significant antipsoriatic effects, superior to 13 and comparable to the positive control GSK2981278, without obvious toxicity. Furthermore, we elucidated molecular mechanism of action for inverse agonist 5a and agonist 1e by means of molecular dynamics (MD) simulation. In summary, 5a holds great promise as a novel antipsoriatic drug candidate.