ACS Medicinal Chemistry Letters最新文献

Water-soluble fullerene derivatives represent emergingmolecularnanomaterials for antiviral drug discovery, yet their target selectivityagainst SARS-CoV-2 proteins remains insufficiently defined. Here,four functionalized [60]fullerenes, C₆₀(OH)₂₄, C₆₀ser, C₆₀ALA, and C₆₀Trp, wereevaluated as binders of key SARS-CoV-2 targets involved in viral entryand replication: spike glycoprotein, papain-like protease, 3CL mainprotease, and RNA-dependent RNA polymerase. Microscale thermophoresisrevealed distinct target-dependent binding profiles governed by fullerenefunctionalization. The C₆₀Trp fullerene was the most activederivative, binding Spike with nanomolar affinity (K_d =94.8 nM) and showing micromolar affinity toward papain-like proteaseand 3CL main protease. Docking and molecular dynamics simulationssupported the preferential interaction of C₆₀Trp with thespike protein cavity through combined fullerene cage complementarityand polar interactions with lysine and arginine residues. The testedderivatives showed low cytotoxicity in A549 cells, and C₆₀Trp was efficiently internalized. These findings identify tryptophan-functionalized[60]fullerene as a promising multivalent scaffold for SARS-CoV-2 proteintargeting.

Class IIa histonedeacetylases (HDACs) are attractive therapeutictargets due to their specialized regulatory functions and restrictedexpression patterns. Recent studies identified HDAC4 and HDAC7 ascritical regulators of Th17-cell differentiation, acting through distincttranscriptional mechanisms to promote Th17 lineage commitment. Buildingon these findings, we designed, synthesized, and characterized a seriesof selective HDAC4/7 inhibitors derived from the Class IIa scaffoldTMP269. Structure-guided optimization of the metal-proximal and hydrophobic-bindingregions generated analogs with improved potency and enhanced isoformselectivity. Luciferase-based transcriptional assays, protein-bindingstudies, and molecular docking analyses revealed distinct structure–activityrelationships that govern HDAC4 versus HDAC7 selectivity. Severalcompounds exhibited potent and selective inhibition of HDAC4- or HDAC7-dependenttranscriptional activity, providing valuable chemical probes to dissectthe individual functions of these enzymes in Th17 biology. These next-generationinhibitors establish a foundation for developing targeted therapiesfor Th17-driven inflammatory disorders, including inflammatory boweldisease.

AI/ML-based tools for generative and predictive modelinghave becomeimportant contributors to small molecule drug discovery, enablingvirtual compound design and ADME profiling prior to synthesis. Alongsidethese methods, simpler nonlearned strategies based on direct SMILESmanipulation remain useful, particularly for low data targets. Hereinis described a method for fragment optimization in which charactersof a SMILES string are systematically replaced with alternative SMILESpatterns to generate atom-type swaps, ring expansion/contraction,cyclization, ring opening, and fragment grafts. The method was initiallyimplemented as a KNIME workflow and demonstrated on fragment-to-leadoptimization of fragments from several programs. A fully open-sourcecounterpart written in Python utilizing AutoDock Vina is also provided.Together, these tools are used in parallel with alternative open-sourceand commercial solutions to accelerate fragment-to-lead optimizationthrough iterative in silico design and profiling,and require no AI/ML or proprietary licensing for the open sourcepython version.

CYP8B1 has been identified as a potential target forthe treatmentof metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD)and type 2 diabetes (T2D). CYP8B1 enzyme inhibitor 1 wasdiscovered from a high-throughput screen of our compound collection;however, its poor metabolic stability prevented further in vivo evaluation.Leveraging structure-based drug design, metabolite identificationand metabolic stability-guided DMPK optimization, and library synthesisto rapidly expand SAR, we identified compound 9 withsubstantially improved DMPK properties. Compound 9 showedrobust in vivo CYP8B1 inhibition in mice and provided the foundationfor further optimization of this class of CYP8B1 inhibitors.

The advent of single-electron, nickel-mediated cross-couplingreactionshas fundamentally transformed how carbon bonds can be forged and isnow a mainstay of modern synthesis and medicinal chemistry. Nickelis a prevailing transition metal that facilitates these innovations,and yet despite its obvious competence, standardized practices regardingNi/ligand preparation and administration, as separate entities oras a single precomplex or catalyst, have not been systematically established.This study investigates the synthesis, isolation, and efficacy ofsimple, ligated Ni(II) precatalysts (NiPCs) to expedite and standardizeprotocols for contemporary single-electron nickel-mediated cross-couplingreactions. We demonstrate the effectiveness of a library of isolatedNiPCs in commonly used singleton transformations and high-throughputexperimentation (HTE) setups with broad application to pharmaceuticalchemistry. By illuminating the practical rules that govern NiPC synthesisand administration, this work equips the community with an actionableunderstanding to enable wide, normalized adoption of simple NiPC methods.

Here we report the applicability of a hotspot-centricapproachfor de novo computational design of l-peptidesbased on crystal structures of antigen–antibody complexes.Broadly neutralizing antibodies (bnAbs) FI6v3 and CR9114, which targetinfluenza A virus hemagglutinin (HA), guided the peptide design. Disembodiedhotspot residues from these bnAbs were selected and anchored ontoknown peptide scaffolds (≤35 amino acids) from the ProteinData Bank (PDB). The top-scoring designs were subsequently synthesized,folded, tested in vitro, and structurally characterizedin complex with HA. The designed peptides demonstrate structural andfunctional mimicry by recapitulating the binding mode of the bnAbson HA and act as inhibitors of low-pH-dependent conformational transitionsin HA that facilitate membrane fusion. These findings demonstratethat hotspot-guided design strategy, previously applied to proteinsand d-peptides, can be effectively extended to l-peptide scaffolds, enabling the development of functional HA inhibitorsinformed by key residues at antigen–antibody interfaces.

The invention in this patent application relates to 6,9-dihydro-5H-imidazo[1,2-a][1,4]diazepine derivatives(or their N-oxides) represented herein by formula 1. These compoundsare peripherally restricted, positive allosteric modulators of oneor more GABA-A receptors. They selectively target the peripheral nervoussystem and body organs and do not substantially penetrate the blood–brainbarrier. Thus, they may provide useful treatment for irritable bowelsyndrome and other related peripheral disorders, including, but notlimited to, functional abdominal pain, chronic idiopathic diarrhea,visceral pain syndromes, inflammatory bowel diseases, bile acid malabsorption,and drug-induced gastrointestinal dysmotility.

Designtime prioritization of central nervous system(CNS) drugcandidates remains a challenge due to the restrictive nature of theblood–brain barrier (BBB) governing brain exposure. Althoughvarious multiparameter optimization (MPO) strategies have guided CNSmedicinal chemistry for over a decade, existing frameworks rely heavilyon heuristic cutoffs and offer limited interpretability across chemicallydiverse scaffolds. Here, we introduce a next generation CNS-MPO framework─Aragen-iMPO,(A-iMPO)─which was developed using 5,129 curated compoundsthrough an integrated workflow combining explainable machine learning,rigorous descriptor selection, and low-dimensional discriminant mapping.This yielded six chemically intuitive features capturing polarity,ionization, size, rigidity, and electronic distribution. The resultingscore provides a transparent discriminant function enabling directcompound prioritization through a simple threshold rule. Across internaland external validation sets, A-iMPO outperformed established CNS-focusedscoring methods while maintaining mechanistic interpretability, providinga practical and design ready tool for CNS drug discovery.

Phosphodiesterase-2 (PDE2) regulates intracellular cAMPand cGMPsignaling and is an important therapeutic target. In this study, weperformed the first virtual screening campaign targeting the allostericGAF-B domain of PDE2 to identify novel allosteric inhibitors. Unlikeconventional virtual screening methods based mainly on calculatedbinding energies, our approach incorporated binding mode analysisto rerank the top 5000 compounds according to the number of hydrogen-bondingand π–π stacking interactions with GAF-B residues.Experimental testing identified various novel PDE2 inhibitors, includingcompound 1 (IC₅₀ = 0.77 μM)selective for PDE2 over other PDE isoforms. The reranking strategyyielded high hit rates of 62%, 51%, 29%, and 14% at inhibition thresholdsof 25%, 30%, 40%, and 50%, respectively. These findings demonstratethat incorporation of binding mode analysis into virtual screeningworkflows can substantially improve hit identification and may providea valuable strategy for future virtual screening campaigns againstPDE2 and other therapeutic targets.

The investigationaldrug zervimesine (CT1812) is an allostericsmall molecule modulator of the sigma-2 receptor (S2R), known as transmembraneprotein 97 (TMEM97), currently in clinical development for Alzheimer’sdisease and dementia with Lewy bodies. In Phase 2 trials, consistentfavorable trends across outcome measures were observed for Alzheimer’sdisease (NCT03507790), dementia with Lewy Bodies (NCT05225415), andanother indication, dry AMD (NCT05893537). The crystal structure ofS2R complexed with zervimesine to 2.74 Å resolution reveals thisinvestigational therapeutic bound in the binding site of S2R analogousto that seen previously with other S2R ligands, and is consistentwith binding affinity data from a S2R competition assay. The structuralinteractions by which zervimesine binds with S2R are illuminated,which may shed light on the potential structure–function relationshipunderlying the favorable effects of zervimesine seen preclinicallyand clinically, and may foster the design of future S2R modulatorsfor neurodegenerative conditions.