Abstract
The large neutral amino acid transporter 1 (LAT1) is a promising anticancer target that is required for the cellular uptake of essential amino acids that serve as building blocks for cancer growth and proliferation. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1. First, a homology model of LAT1 that is based on the atomic structures of the prokaryotic homologs was constructed. Molecular docking of nitrogen mustards (NMs) with a wide range of affinity allowed for deriving a common binding mode that could explain the structure−activity relationship pattern in NMs. Subsequently, validated binding hypotheses were subjected to molecular dynamics simulation, which allowed for extracting a set of dynamic pharmacophores. Finally, a library of ~1.1 million molecules was virtually screened against these pharmacophores, followed by docking. Biological testing of the 30 top-ranked hits revealed 13 actives, with the best compound showing an IC50 value in the sub-μM range.
Highlights
The Large neutral Amino acid Transporter 1 (LAT1, or SLC7A5) is a transmembrane protein belonging to the Heteromeric Amino acid Transporter (HAT) family that is responsible for cellular uptake of hydrophobic amino acids
large neutral amino acid transporter 1 (LAT1) is substantially expressed at the Blood-Brain Barrier (BBB), where it permits the influx of essential amino acids that are indispensable for brain metabolism
Though considerably less potent than 36 and 42, 28 is a cysteine-based LAT1 inhibitor that would be difficult to retrieve through simple similarity-search using 11 or phenylalanine
Summary
The Large neutral Amino acid Transporter 1 (LAT1, or SLC7A5) is a transmembrane protein belonging to the Heteromeric Amino acid Transporter (HAT) family that is responsible for cellular uptake of hydrophobic amino acids (e.g., phenylalanine and tyrosine). LAT1 is substantially expressed at the Blood-Brain Barrier (BBB), where it permits the influx of essential amino acids that are indispensable for brain metabolism. At the BBB, LAT1 mediates the uptake of thyroid hormones, prescription drugs, (e.g., melphalan, gabapentin, and L-DOPA), and metabolites [1,2,3]. For these reasons, LAT1 is a target of interest for brain drug delivery in the treatment of neurological disorders [4]. LAT1 inhibitors act by thwarting the supply of amino acids to cancer cells, impeding the protein synthesis and cellular. H[6o,1w7e,1v8e]r., HBCowHeivsear,loBwC-Haffiisniatylaonwd-anffoinn-istyeleacntdivenosunb-ssetlreactteivoef LsuAbTs1t,raatnedoaf vLeAryT1h,igahndcoancveenrtyrahtiiognh (c>o1n0cmenMtra) tiisorneq(>u1ir0edmtMo a) titsairneqanutiirpedroltiofearatttaivine eafnfeticptrso[l1if9e–r2a1t]iv. eTheeffnecotvse[l1t9y−ro21si]n. eTahneanloogv,eKl YtyTr-o0s3i5n3e (iaSJnPn2Hhaclue-o2mlgl0s,3aKa)nn(Y2cdT)o-il00so.30na56p3cμoa(tnMJePcnHeitrn-a2(nhH0du3T)ms-e(2a2l9en))citscciovealelolpsinno. thIcetianbantiltcsaoeonrrdos(ufHsLpeTlApe-2rTce9t1is),vswceeediiltnlhsthh.aieIbntigtIaoCrlros5ow0ofostuhLf 0pAo.p1Tfr41ce,μaswsnMecidteihnrthaScnee2lcIlgsCerlo5al0swnoadftnh0xd.oe10fn4.0ocμ6agMnrμacMeifntr tcuemllsorasn[d22x]e. nAodgdraitfitotnuamllyo,ras r[2ec2e].nAt pdudbitliiocnatailolyn,raeproecrteendt 1p,u2,b3l-idcaitthioianzroelpeobratseedd1i,r2r,e3v-deirtshibialzeocloevbaalesnedt iinrhreibvietrosrisbl(e3)ctohvaatlsehnot winehdibpiototersnt(3in)htihbaittioshnoowf ehdumpoatnenLtAiTn1hribecitoionnstiotuf theudminanprLoAteTo1liproescoomnsetsitu[2t3e]d. in proteoliposomes [23]
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