ACS Medicinal Chemistry Letters最新文献

The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC₅₀ of 73.61 μM and a K _i of 22 μM. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC₅₀ values between 15.06 and 51.81 μM. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro.

One of the prominent challenges in breast cancer (BC) treatment is human epidermal growth factor receptor (EGFR) overexpression, which facilitates tumor proliferation and presents a viable target for anticancer therapies. This study integrates multiomics data to pinpoint promising therapeutic compounds and employs a machine learning (ML)-based similarity search to identify effective alternatives. We used BC cell line data from the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases and single-cell RNA sequencing (scRNA-seq) information that established afatinib as an efficacious candidate demonstrating superior IC₅₀ values. Next, ML models, including support vector machine (SVM), artificial neural networks (ANN), and random forest (RF), were trained on ChEMBL data to classify compounds with similar activity to the reference drug as active or inactive. The promising candidates underwent computational structural biology assessments for their molecular interactions and conformational dynamics. Our findings indicate that compounds ChEMBL233324, ChEMBL233325, ChEMBL234580, and ChEMBL372692 exhibit potent repressive action against EGFR, underscoring their potential as active antibreast cancer agents.

Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed. The oximes were designed with a halogen substituent that lowers the pK_a and enhances oximate formation. Their synthesis, stability, physicochemical properties, inhibition of native cholinesterases, and in vitro reactivation of organophosphate-inhibited cholinesterases were investigated. A series of C4 and C6 halogenated oximes showed instability and their degradation products were identified, while C3 and C5 oximes exhibited sufficient stability for the evaluation. C3 oximes displayed overall low inhibition of cholinesterases and high reactivation ability of organophosphate-inhibited cholinesterases compared to pralidoxime, indicating the significant impact of halogen substitution on reactivation ability.

The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC₅₀ of 73.61 μM and a K_i of 22 μM. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC₅₀ values between 15.06 and 51.81 μM. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro.

Organophosphorus compounds are highly toxic irreversible inhibitors of cholinesterases, causing the disruption of cholinergic functions. Treatment of poisoning includes causal antidotes (oximes) used as reactivators of inhibited cholinesterases, such as pralidoxime. In this work, new halogenated oxime reactivators derived from pralidoxime were developed. The oximes were designed with a halogen substituent that lowers the pK _a and enhances oximate formation. Their synthesis, stability, physicochemical properties, inhibition of native cholinesterases, and in vitro reactivation of organophosphate-inhibited cholinesterases were investigated. A series of C4 and C6 halogenated oximes showed instability and their degradation products were identified, while C3 and C5 oximes exhibited sufficient stability for the evaluation. C3 oximes displayed overall low inhibition of cholinesterases and high reactivation ability of organophosphate-inhibited cholinesterases compared to pralidoxime, indicating the significant impact of halogen substitution on reactivation ability.

Newly synthesized naphthalene-based twisted intramolecular charge transfer (TICT) molecules show 8.5- and 2.6-fold increases in fluorescence intensity upon binding with protein aggregates in comparison with the fluorescence enhancement for thioflavin T (ThT). The dissociation constant (K_d) values of these compounds with bovine serum albumin (BSA) aggregates are in the 145–176 nM range, which is 10³ times lower than that of ThT. Along with the strong binding propensity, these molecules are also capable of measuring protein aggregate (BSA) concentration in the 500 to 5 pM level. Interestingly, one of the synthesized molecules was also able to bind with the intracellular protein aggregates.

[This corrects the article DOI: 10.1021/acsmedchemlett.4c00317.].

Newly synthesized naphthalene-based twisted intramolecular charge transfer (TICT) molecules show 8.5- and 2.6-fold increases in fluorescence intensity upon binding with protein aggregates in comparison with the fluorescence enhancement for thioflavin T (ThT). The dissociation constant (K _d ) values of these compounds with bovine serum albumin (BSA) aggregates are in the 145-176 nM range, which is 10³ times lower than that of ThT. Along with the strong binding propensity, these molecules are also capable of measuring protein aggregate (BSA) concentration in the 500 to 5 pM level. Interestingly, one of the synthesized molecules was also able to bind with the intracellular protein aggregates.

Assessing the binding mode of drug-like compounds is key in structure-based drug design. However, this may be challenged by factors such as the structural flexibility of the target protein. In this case, state-of-the-art computational methods can be valuable to explore the linkages between structural and pharmacological data. Following this strategy, extended molecular dynamics simulations and thermodynamic integration calculations are used to examine the binding of the potent antiviral inhibitor M090 and related pinanamine-based analogues, covering a 250-fold difference in inhibitory potency to the influenza A hemagglutinin, which is essential for virus entry and membrane fusion. This analysis has disclosed the hydrophobic shielding effect played by the 3-cyclopropylthiophene moiety in M090. Furthermore, the results support the negative effect of the resistance-induced E74₂ → D mutation, which should weaken the binding by increasing the structural flexibility of the L2-BS loop. The results pave the way to exploration of the antiviral activity of novel compounds.