Article

Designing L-type Amino Acid Transporter 1-targeting Cancer

Theranostic Radiopharmaceuticals: A Molecular Docking

Simulation

Holis Abdul Holik^1*, Arifudin Achmad², Faisal Maulana Ibrahim¹, Angela Alysia Elaine¹,

Jonathan Stefanus¹, B.S. Ari Sudarmanto³, Achmad Hussein S. Kartamihardja²

¹Department of Pharmaceutical Analysis & Medicinal Chemistry, Faculty of Pharmacy, Universitas

Padjadjaran; Hegarmanah, Jatinangor, Sumedang 45363, West Java, Indonesia

²Department of Nuclear Medicine and Molecular Theranostics, Faculty of Medicine, Universitas

Padjadjaran, Bandung 40162, West Java, Indonesia

³Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy,

Universitas Gadjah Mada, D.I. Yogyakarta 55281, Indonesia

Abstract

L-type amino acid transporter 1 (LAT1) is a potential pan-cancer theranostic molecular target. The LAT1

inhibitory potencies of eight theranostic radiopharmaceuticals designed based on a potent LAT1 inhibitor

ADPB (in vitro predicted pIC₅₀6.19), were estimated in molecular docking simulations. The designs

comprised ADPB as a carrier molecule with/without 6-aminohexanoic acid (Ahx) linker, a chelating agent,

and a radiometal (68Ga or 177Lu). JPH203, the most potent LAT1 inhibitor (predicted pIC₅₀7.22), was utilized

as a benchmark compound. A set of known LAT1 ligands (n = 15) were first docked into LAT1 to build the

docking protocol with the software Molecular Operating Environment (MOE). Adding a linker improved the

LAT1 inhibitory potency of DOTA-conjugated and NODAGA-conjugated ADPB-based theranostic

radiopharmaceutical designs. 177Lu-DOTA-Ahx-ADPB has the exceptional LAT1 inhibitory potency

(predicted pIC₅₀51.55 ± 17.06) while 177Lu-DOTA-ADPB, its non-linker counterpart, has LAT1 inhibitory

potency significantly higher than the native JPH203. The evaluation of docking poses and quantitative

analysis for both 177Lu-DOTA-Ahx-ADPB and 177Lu-DOTA-ADPB have strong bonds with key amino acids

on the LAT1 binding pocket, particularly Asn258, Tyr259, and the gating residue Phe252. Our findings

provide a quantitative and illustrative understanding of the LAT1 inhibitory potency of LAT1-targeting

theranostic radiopharmaceutical designs relevant to the rational design of pan-cancer radiotheranostic

drugs.

Keywords: Chelating agent, LAT1, pan-cancer, Molecular Operating Environment (MOE), theranostic

radiopharmaceutical,

*

Corresponding author

Email addresses: holis@unpad.ac.id

DOI: https://doi.org/10.22437/chp.v9i2.44633

Received August 28^th2025; Accepted October 07^th2025; Available online December 31^st2025

(https://creativecommons.org/licenses/by/4.0 )

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Graphical Abstract

Introduction

(CXCR4) were considered potential pan-

The global burden of cancer is expected to

be 28.4 million cases in 2040, equal to a 47%

rise from the current figures [1]. Thus,

earlier tumor entity characterization and

cancer

radiopharmaceuticals

targets,

and

theranostic

developed

promising

accordingly

demonstrated

preliminary clinical translation (e.g., ⁶⁸Ga-

metastasis

important

detection

for accurate

are

increasingly

staging and

FAPI-04, ⁶⁸Ga-pentixafor). However, several

inherent

challenges

remain,

as

FAP-

personalized cancer therapy. Systematic

integration of diagnostic nuclear imaging

and targeted nuclear therapy using a single

targeting might be less reliable in non-

desmoplastic tumors [4], while CXCR4-

targeting might be less useful in several

molecular-targeting

compound

(termed

solid

tumors

than

in

hematologic

"radiotheranostics") is now commenced

thanks to the validation of molecular cancer

targets (e.g., prostate-specific membrane

antigen (PSMA), somatostatin receptors

(SSTRs)) and the rapid development of

malignancies [5].

L-type amino acid transporter 1 (LAT1), a

Na⁺-independent bidirectional amino acid

transporter with broad substrate specificity

toward large neutral hydrophobic/aromatic

amino acids and other substrates such as L-

DOPA, melphalan, and gabapentin, has long

advanced

radiopharmaceuticals

carrier molecules, radiometals, chelating

agents, and pharmacokinetic-modifying

chemical

scaffolds

for

(cancer-specific

been

proliferation

proven

[6].

influential

in

cancer

recent

Furthermore,

linkers). In addition, successful clinical

translation has been shown in advanced

evidence validates that LAT1 satisfies the

requirements as a pan-cancer target for

being: 1) consistently overexpressed in the

plasma membrane of all types of cancer

cells, 2) limited expressed in normal cells

prostate

neuroendocrine

cancer

and

malignancies

gastrointestinal

[2,3].

Recently, fibroblast activation protein (FAP)

and C-X-C motif chemokine receptor 4

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Chempublish Journal, 9(2) 2025, 329-346

[7,8], and 3) instrumental in promoting

multiple cancer hallmarks [9]. L-[3-¹⁸F]-α-

methyltyrosine (¹⁸F-FAMT), a LAT1-specific

PET probe, has been demonstrated to be

cancer-specific and able to discriminate

malignant lesions from non-cancerous

lesions, including inflammation [10,11]. The

low background uptake in ¹⁸F-FAMT PET

bromo-4-methoxybenzyl)-L-cysteine

(predicted pIC₅₀4.48) are two potent LAT1

inhibitors

pharmacophore-based

libraries containing

revealed

through

screening

million

dynamic

of

small

1.1

molecules [18]. ADPB has several properties

suitable to be developed as LAT1-targeting

theranostic radiopharmaceuticals, i.e., 1) a

images

expression of LAT1 in normal tissues [7].

Until recently, several "LAT1-specific"

also

confirmed

the

lacking

simple

and

similar

structure

to

L-

phenylalanine (a system-L substrate and

the most commonly used compound to

radiopharmaceuticals have been developed

evaluate

LAT1

transport

activity),

2)

(e.g.,

¹⁸F-FAMT

,

L-[2-¹⁸F]-α-

possession of halogen atoms on its

hydrophobic side chain similar to LAT1 non-

transportable

triiodothyronine

tetraiodothyronine

conjugation possibility with a chelating

methylphenylalanine (¹⁸F-FAMP) [12], (S)-2-

amino-3-[3-(2-¹⁸F-fluoroethoxy)-4-

blockers

(T3)

(T4))

(e.g.,

and

iodophenyl]-2-methylpropanoic acid (¹⁸F-

FIMP)

[13],

4-borono-2-[¹⁸F]-fluoro-L-

[19],

and

3)

phenylalanine (¹⁸F-FBPA) [14], 2-[¹⁸F]-2-

fluoroethyl-L-phenylalanine (¹⁸F-FELP) [15]

and ¹⁸F-NKO-035 [16,17]. However, even

though some among them showed clinical

potential, none were genuinely designed as

agent

or

a

pharmacokinetic-modifying

simple 1-ethyl-3-(3-

(EDC)

and N-hydroxysulfosuccinimide (NHS) ester

coupling chemistry (Figure 1) [20].

Furthermore, the recent availability of a

linker

via

a

dimethylaminopropyl)carbodiimide

a

theranostic

radiopharmaceutical.

Therefore, the design of new compounds is

needed to develop and apply theranostic

radiopharmaceuticals for clinical use in

cancer patients.

high-resolution

structure in

conformation opens the possibility of

human

an

LAT1

crystal

outward-facing

screening new inhibitors [21].

(S)-2-amino-4-(3,5-dichlorophenyl)butanoic

acid (ADPB, predicted pIC₅₀6.19) and S-(3-

Figure 1. The chemical structure of LAT1 inhibitors (a) ADPB; (b) JPH203; (c) and 3,5-L-diiodotyrosine/Diiodo-

Tyr) and (d) LAT1 substrate (L-phenylalanine).

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In this study, LAT1-targeting theranostic

radiopharmaceutical scaffold was designed

as follows: ADPB as the carrier molecule; a

Preparation

Ligands for Computational Study.

of

Radiopharmaceutical

The general schematic design

theranostic radiopharmaceutical

compounds for computational study are

illustrated in Figure 2. The compounds

of

hydrophobic,

aminohexanoic acid (Ahx) [22]; bifunctional

chelating agents (1,4,7,10-

flexible

linker

6-

tetraazacyclododecane-1,4,7,10-tetraacetic

acid (DOTA) or 1,4,7-triazacyclononane-

were

designed

with

the

following

components: a carrier molecule (ADPB or

JPH203), a chelator (DOTA, NOTA, and

NODAGA), and a radiometal (⁶⁸Ga or ¹⁷⁷Lu).

All designs were built with or without a

1,4,7-triacetic

acid

(NOTA)

or

1,4,7-

triazacyclononane,1-glutaric acid-4,7-acetic

acid (NODAGA)), and theranostic pair

radiometals

(⁶⁸Ga

or

¹⁷⁷Lu)

[23].

A

pharmacokinetic-modifying

linker

(6-

substantial modification in the chemical

structure of the carrier molecule, especially

aminohexanoic acid (Ahx)). The amine

group of the carrier molecule was modified

to form an amide bond with a carboxylate

group of chelator or linker to allow

the addition of

complex and

a

radiometal-chelator

linker/spacer, might

drastically change the binding affinity of an

inhibitor. Therefore, the current molecular

docking simulations aim to evaluate the

LAT1 inhibitory potency of ADPB-based

theranostic radiopharmaceuticals. JPH203

(Nanvuranlat, (S)-2-amino-3-(4-((5-amino-2-

phenylbenzo[D]oxazol-7-yl)methoxy)-3,5-

dichlorophenyl)propanoic acid), the most

conjugation

via

simple

EDC–

N-

hydroxysulfosuccinimide ester chemistry

later in the experimental synthesis. Of note,

JPH203 has two free amide groups; thus,

conjugation

generates

(JPH203_x, JPH203_y, and JPH203_z; see

Supp. Data S2). Representative 2D and 3D

designs were illustrated in Supp. Data S2.

All three chelators are compatible with ⁶⁸Ga

radiolabeling, while ¹⁷⁷Lu radiolabeling was

with

three

a

chelating

agent

different

conjugates

potent LAT1 inhibitor (predicted pIC₅₀

=

7.22) [24], was utilized as a comparison and

the benchmark for LAT1 inhibitory potency.

only

evaluated

in

DOTA-conjugated

Materials And Methods

designs. A complete list of all theranostic

radiopharmaceutical designs is in Supp.

Data S3.

The workflow of our molecular docking

simulations is illustrated in Supp. Data S1.

Computational Study Software

Preparation of Target Molecule

Softwares used in this computational study

are MarvinSketch (MarvinSuite Europium 7

The heterodimer complex of the human

LAT1-subunit 4F2hc was downloaded from

the Protein Data Bank of the Research

Collaboration for Structural Bioinformatics

website (www.rcsb.org, PDB ID: 7DSQ). The

3D complex structure of human LAT1,

(19.21.7)

https://www.chemaxon.com) for build 2D

structure of ligands and Molecular

ChemAxon,

Operating Environment v2020.09 (MOE)

software (Chemical Computing Group,

Montreal, QC, Canada) for build 3D

structure of ligands and semi-empirically

optimize the ligands.

newly

solved

from

cryo-electron

microscopy images (resolution 3.4 Å), is in

an outward-facing conformation with 3,5-L-

diiodotyrosine (Diiodo-Tyr, predicted pIC₅₀

= 5.10) as a native substrate bound on its

substrate binding pocket [21]. Before

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preparation, Diiodo-Tyr was removed from

the LAT1 substrate binding pocket. Then,

the preparation of the LAT1 was performed

using the QuickPrep functionality in MOE.

During this process, protonation states

were determined, missing hydrogen atoms

were added, missing amino acid sequences

were modeled, and the resulting complex

structure was energetically minimized. The

side chain of amino acid residues in the

LAT1 binding pocket was made flexible,

while the main chain remained rigid. Water

molecules were removed from the LAT1

complex after the preparation step.

phenylalanine, Supp. Data S5) were each

docked into the 3D structure of LAT1 using

all five scoring functions. First, docking

scores (S, unit: kcal/mol) of each known

LAT1 ligand were plotted in a linear Pearson

correlation

analysis

toward

their

corresponding predicted pIC₅₀values. Then,

the scoring function producing the best

correlation coefficient (R²) between these

two

variables

was

selected

for

the

subsequent

docking

simulations.

The

corresponding linear regression formula

(predicted pIC₅₀= a(S) + b) was eventually

used to estimate the LAT1 inhibitory

potency

radiopharmaceutical design.

of

each

theranostic

Validation of Docking Pose

To validate that the binding pocket did not

experience a significant change after the

preparation, pose validation was performed

by redocking Diiodo-Tyr into the post-

prepared LAT1 in several simulations using

multiple parameters. The docking poses of

Diiodo-Tyr in the post-prepared LAT1

binding pocket were superposed against its

The data of known LAT1 ligands were

obtained from the ChEMBL database

(www.ebi.ac.uk/chembl/), including the

detailed 2D structure and predicted pIC₅₀

against LAT1 from previously published in

vitro or in vivo experiments. In addition, an

identical preparation method was applied to

these known LAT1 ligands. Trial docking also

generated a LAT1 inhibition pharmacophore

to which the 3D docking pose will be

evaluated.

original

pose.

The

root-mean-square

distance (RMSD) < 2 Å difference between

the most rational post-preparation pose

and the original pose was considered no

significant departure.

Docking Protocol, Docking Pose Evaluation,

and Quantitative Analysis

The docking protocol was generated by

varying the configuration for defining the

binding site, the presence of crystallographic

waters for hydrogen-bond mediation (WC),

ligand and receptor protonation states (ph4),

Refinement Trial.

MOE software package allows one to

choose one of five scoring functions

available (London dG, ASE, Affinity dG,

Alpha

HB,

and

GBVI/WSA

dG)

to

and

the

pose

placement

algorithm

approximate the binding affinity (Gibbs free

energy, ΔG, unit: kcal/mol) between two

molecules after they have been docked

(algorithm of each scoring function is

explained in Supp. Data S4). Trial docking

(placement) in MOE. The results of the

docking protocol variations were then

calculated using root-mean-square deviation

(RMSD), and the protocol with the lowest

RMSD was selected. Molecular docking

was

performed

to

approximate

the

simulations

of

theranostic

quantitative docking results closer to the

actual LAT1 inhibition using known LAT1

ligands retrieved from the literature. Known

LAT1 ligands (n = 15, including JPH203 and

radiopharmaceutical designs' binding to

LAT1 were performed using the triangle

method as a placement method with a

timeout of 300 s, London dG scoring function

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in 1,000 iterations, and the exploration for

best conformation was repeated 30 times.

Force field was used as a refinement method

further analysis. The criteria used were

based on their more negative S values, most

rational poses (carrier molecule inside the

binding pocket), and best intermolecular

interactions with key amino acid sequences

on the LAT1 binding pocket.

by

conformations

radiopharmaceutical design were chosen for

applying

MMFF94x.

The

best

of each

theranostic

Figure 2. Schematic figure of theranostic radiopharmaceutical designs. (Notes: aa = amino acids, BFCA =

bifunctional chelating agent.

Evaluation of the Docking Poses and

Quantitative Analyses

The intermolecular interactions of key

amino acid residues on LAT1 binding pocket

with each theranostic radiopharmaceutical

design in its particular pose were visualized

and analyzed in 2D using Biovia Discovery

Studio 2016 (Biovia Dassault Systèmes, San

Diego, US) and in 3D using MOE. Those key

amino acid residues are Phe252 (F252, a

gating element), Trp257 (W257), Tyr259

(Y259), and ASN258 (N258) [25]. The

docking poses in MOE were also used to

confirm LAT1 inhibition pharmacophore

occupancy of each pose and predict the

linker's role toward the conformity of each

theranostic radiopharmaceutical design.

The .pdb files obtained were reconstructed

for further 3D visualization using Biovia

Discovery Studio 2016.

LAT1 inhibitory potency (estimated predicted

pIC₅₀) of ADPB-based and JPH203-based

theranostic radiopharmaceuticals (predicted

pIC₅₀) was compared accordingly (based on

their radiometal and linker). The in vitro

predicted pIC₅₀of native ADPB (6.19) and

native JPH203 (7.22) was set as the lower limit

in

finding

which

theranostic

radiopharmaceutical design has better LAT1

inhibition potential [19]. Statistical analyses

were made to compare the central tendency

values (mean or median) of the two unpaired

groups (Students' t or Mann-Whitney U test,

where applicable). The statistical significance

level was p < 0.05 (95% confidence interval).

Statistical analysis was performed using

GraphPad

Prism

software

(version

6,

GraphPad Software, La Jolla CA, USA.

www.graphpad.com).

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Figure 3. The 3D structure of human LAT1 with Diiodo-Tyr occluded the LAT1 substrate binding pocket.

Overlaid image (box) of Diiodo-Tyr docking pose post-preparation (orange) and its original pose (light green)

during pose validation

Evaluation of the Docking Poses and

Quantitative Analyses

ADPB-based and JPH203-based theranostic

radiopharmaceutical designs containing

¹⁷⁷Lu radiometal demonstrated a higher

LAT1 inhibitory potency than those with

⁶⁸Ga radiometal based on predicted pIC₅₀

value (Supp.Data S3). ADPB-based and

JPH203-based radiopharmaceuticals with

LAT1 Inhibitory Potency of ADPB-based

Theranostic Radiopharmaceutical Design. All

theranostic radiopharmaceutical designs in

this study demonstrated negative docking

scores (Supp. Data S3). Generally, ADPB-

the

radiometal

¹⁷⁷Lu

have

estimated

based

theranostic

radiopharmaceutical

predicted pIC₅₀values in the range of 51.57

to 87.12, while APBD-based and JPH203-

designs did not exhibit a higher LAT1

inhibitory potency than the JPH203-based

ones (Supp. Data S7). ¹⁷⁷Lu-DOTA-Ahx-

based

radiopharmaceuticals

with

the

radiometal ⁶⁸Ga have estimated predicted

pIC₅₀values in the range of 1.96 to 17.48. In

addition, adding an Ahx linker improves

LAT1 inhibitory potency of ADPB-based

designs, except if a NOTA chelator was used

(Figure 4). However, such improvement

was not observable in JPH203-based

designs (Supp. Data S7). Therefore, to

analyze further the extraordinary LAT1

inhibitory potency of ¹⁷⁷Lu-DOTA-Ahx-ADPB

ADPB,

¹⁷⁷Lu-DOTA-ADPB,

and

⁶⁸Ga-

NODAGA-Ahx-ADPB were the only three

among eight ADPB-based theranostic

radiopharmaceutical designs having a LAT1

inhibitory potency better than their native

form (ADPB). However, based on statistical

comparison of LAT1 inhibitory potencies

among

ADPB-based

theranostic

radiopharmaceutical, native ADPB, and

native JPH203, ¹⁷⁷Lu-DOTA-Ahx-ADPB and

and

¹⁷⁷Lu-DOTA-ADPB,

subsequent

¹⁷⁷Lu-DOTA-ADPB

demonstrated

LAT1

analyses involved ⁶⁸Ga-DOTA-Ahx-ADPB

and ⁶⁸Ga-DOTA-ADPB.

inhibitory potency significantly higher than

native JPH203 (P value = 0.0044 for ¹⁷⁷Lu-

DOTA-Ahx-ADPB and P value = 0.00227 for

¹⁷⁷Lu-DOTA-ADPB) (Figure 4, Supp. Data S8).

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Figure 4. Estimated predicted pIC₅₀of ADPB-based theranostic radiopharmaceutical designs; n = 5 for

each design, n.s. statistically not significant, ** p <0.001, *** p <0.0001.

target. In this work, we proposed theranostic

Intermolecular interactions with amino

acids residue in LAT1 substrate binding

pocket

radiopharmaceutical designs based on a LAT1

inhibitor ADPB and computed its LAT1

inhibitory

potentials

through

molecular

docking simulations. The selection basis of

ADPB as the carrier molecule was multiple.

First, ADPB (predicted pIC₅₀= 6.19) has been

validated experimentally as a potent LAT1

inhibitor with an inhibition potential higher

than natural LAT1 substrates (essential amino

acids, neutral amino acids with large side

chains, e.g.: Leu, Val, Ile, Phe, Trp, His, Met, Tyr).

¹⁷⁷Lu-DOTA-Ahx-ADPB

and

¹⁷⁷Lu-DOTA-

ADPB have hydrogen bonds with key amino

acid residues on the LAT1 binding pocket,

particularly Asn258, Tyr259, and the gating

residue Phe252. ⁶⁸Ga-DOTA-Ahx-ADPB and

⁶⁸Ga-DOTA-ADPB, on the other hand, lack

strong intermolecular interactions based on

the hydrogen bond formed between LAT1

and these compounds as ligands (Table 1,

Figure 5). The 3D docking poses and

detailed interactions are provided in Figure

6, Figure 7, and mol2 3D molecular model

files in Additional Files.

The

ADPB

structure

is

similar

to

L-

phenylalanine, the most widely used LAT1

natural substrate in the LAT1 transport

evaluation and structure-based discovery for

LAT1 inhibitors [18]. The other reason is that

ADPB possesses two halogen atoms, similar to

JPH203, the most potent LAT1 inhibitor, and

other high-affinity LAT1 ligands (e.g., T3, T4,

Diiodo-Tyr) (Figure 1).

LAT1 has been reported overexpressed on

the

cancer

cell

membranes

in

all

malignancies and prognostic for poor

clinical outcomes [26,27]. The LAT1

expression, however, has been confirmed

limited in normal tissue [7]. Therefore, LAT1

is a promising pan-cancer radiotheranostic

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Table 1. Intermolecular interaction between ADPB-based theranostic radiopharmaceuticals and key amino acids residues in the LAT1 substrate

binding pocket

1

2

3

4

5

6

ADPB-based

theranostic

Estimated

predicted pIC₅₀

Conventional

Hydrogen

Bond

Other

Carbon Hydrogen

Bond

π‒π

Van der Waals force

π-Alkyl

radiopharmaceutical

designs

interactions

(±SD)

interaction

¹⁷⁷Lu-DOTA-Ahx-ADPB

51.55

ASN258,

TRP257

PHE252,

ASN258,

TYR259,

ASP116,

GLU136,

SER401

PHE403, CYS407, PHE262,

LYS132, VAL408, LEU349,

LEU251, ILE397, THR62,

SER338, VAL148, GLY65,

SER66, GLY67, TYR264, SER96,

SER144, TRP405, GLY255,

PHE400, GLY256

PHE252,

VAL148,

ILE147,

PHE400

‒

ARG141,

±17.06

(Pi-Sigma)

ASN404

¹⁷⁷Lu-DOTA-ADPB

⁶⁸Ga-DOTA-Ahx-ADPB

⁶⁸Ga-DOTA-ADPB

19.42

ASN258,

GLY256,

TYR259,

GLY255,

ASP116,

TRP257, ARG141, ILE140,

ILE397, SER66, GLY65, ILE63,

GLY67, SER144, THR62,

PHE252,

VAL148,

ILE147,

‒

±7.58

ASN404

PHE403, PHE262, SER342,

LYS132, CYS407, VAL408

PHE400,

6.47

THR62

GLY65

PHE400

PHE252, ASN258, VAL70,

ILE397, THR71, VAL151,

TYR259

±0.27

PHE394, VAL148, ASN404,

GLY256, SER144, GLY255,

SER338, ILE63, ILE147, GLY67

‒

2.64

SER66,

THR71, GLY65,

GLY67,

TRP257,

PHE252, ASN258, GLY74,

VAL70, ILE64, THR62, SER338,

VAL148, TYR259, LEU251,

ILE147, VAL408, PHE400,

ALA253, VAL151, ILE397,

LYS453, PHE394, SER249

GLY255,

±0.35

ILE63

GLY256 (Pi-

donor)

TRP405

Note: Key amino acid residues were typed in bold. Amino acid residues typed in bold-italic were also mentioned in literature

as important gating components. Numbers in the first row indicate the interaction strength from high to low.

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Figure 5. Intermolecular interaction between ADPB-based theranostic radiopharmaceuticals and key amino

acids residues in the LAT1 substrate binding pocket. Key amino acid residues were mark with red circle.

The non-covalent interaction of halogen

atoms has been experimentally proven

essential in LAT1 ligand recognition and in

making polar contacts with the amino acid

side chains, especially for small molecules

like ADPB [19]. Despite relatively smaller

and more simple, ADPB retains LAT1

inhibitory potency comparable to other

structurally fit within the LAT1 binding pocket,

unfortunately, its large side chain with multiple

rings renders it rigid and large, thus leaving no

room for additional chemical scaffold required

for theranostic moieties. On the other hand,

ADPB is still considerably smaller than JPH203,

even though it possesses an extra carbon

length compared to L-phenylalanine and

Diiodo-Tyr. This feature allows ADPB to satisfy

the LAT1 inhibition pharmacophore while

potential

(predicted pIC₅₀= 6.92), JX-075 (predicted

pIC₅₀= 6.78), JX-119 (predicted pIC₅₀

LAT1

inhibitors, e.g.,

JX-078

=

providing

enough

space

for

additional

6.23)[7], and SKN103 (predicted pIC₅₀= 5.70)

[28].

chemical scaffolds [18]. Furthermore, ADPB

has a single primary amine capable of

conjugation

using

simple

EDC-NHS

JPH203 (KYT0353), the most potent LAT1

inhibitor (predicted pIC₅₀7.22) to date, has

been evaluated using in vitro and in vivo

models of various cancers and is currently

being challenged in phase II clinical trial for

cholangiocarcinoma [24]. Even though

JPH203 was cleverly designed to be

conjugation chemistry. On the contrary,

JPH203 possesses two primary amines; thus,

impractical to be developed as a theranostic

radiopharmaceutical

using

a

similar

conjugation method. In addition, the known

338

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Chempublish Journal, 9(2) 2025, 329-346

low solubility of JPH203 might hamper

conjugation reactions [25,29].

Figure 6. The 3D docking poses of ADPB-based theranostic radiopharmaceutical designs.

Hydrophobic (green shade) and hydrophilic (purple shade) regions of the radiopharmaceutical

designs

It is also important to note that the outer

access to the LAT1 binding pocket is

partially covered by a bulky extracellular

domain 4F2hc subunit (Figure 3). Thus, a

theranostic radiopharmaceutical conjugate

targeting the LAT1 binding pocket must also

be equipped with some degree of flexibility.

Therefore, we added 6-aminohexanoic acid

(Ahx) linker as a flexible methylene bridge

between the chelating agent and the carrier

molecule (Figure 2, Supp. Data S2). Ahx

addition has proven useful in improving

solubility and cell membrane permeability in

various conjugates (from peptides to

antibodies). More importantly, the presence of

Ahx in the structures of the conjugate neither

improves nor decreases biological activity but

significantly improves the interaction with the

molecular target [22]. The six carbon-length of

Ahx also provided just enough distance

between ADPB and chelator-metal complex to

allow the overall conjugate to fit in the LAT1

binding pocket.

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Chempublish Journal, 9(2) 2025, 329-346

Figure 7. The 3D docking poses of ADPB-based theranostic radiopharmaceutical designs. Relative position

against transmembrane helix 1 or TM1 (light green and brown) and transmembrane helix 6 or TM6 (cyan and

purple) domains (left). Intermolecular interactions with key amino acid residues (right).

Eventually, we added DOTA, NOTA, and

NODAGA as chelators to facilitate

NODAGA were recently reported as potential

BFCA for ^99mTc/¹⁸⁶Re radiometal theranostic

pair [32]; unfortunately, we could not

successfully parameterize these metal prior

radiolabeling with theranostic radiometals.

DOTA is regarded as an "industry standard"

chelating agent due to its compatibility with

useful radiometals such as ¹⁷⁷Lu, ^86/90Y, ¹¹¹In,

^44/47Sc, ^212/213Bi, and ^67/68Ga [23]. On the other

hand, NOTA is considered a good chelator

agent for the small ion Ga³⁺, which fits well

into its small cavity. NOTA is also promising

to

ligand

preparation

before

docking

simulations.

Hence,

we

designed the

theranostic radiopharmaceuticals using ¹⁷⁷Lu

and

⁶⁸Ga,

the

most

commonly

used

theranostic radionuclide pair. Even though

¹⁷⁷Lu also has diagnostic properties (-ray

emitter for SPECT camera), ⁶⁸Ga allows much

better image resolution (with PET camera) [2].

for

the

clinical

translation

due to

of

rapid

radiopharmaceutical

kits

radiolabeling at room temperature and mild

pH to give complex with high

thermodynamics and excellent in vivo

stability [30]. NODAGA (a NOTA-derivative)

offers a similarly high-stability complex with

⁶⁸Ga but adds an extra negative charge via an

additional carboxyl group [31]. NOTA and

In our molecular docking simulation, in vitro

data of LAT1 inhibitors was used in trial

docking 1) to generate a pharmacophore of

LAT1 inhibition and 2) to finely select the

refinement algorithm (scoring function) and

build the final docking protocol for the main

a

340

H.A. Holik., et al.

Chempublish Journal, 9(2) 2025, 329-346

study. Five scoring functions available in MOE

employ different mathematical approaches

to estimate the molecular interactions.

Therefore, trial docking simulations were

performed with each scoring function. The

London dG algorithm was the scoring

function that produced docking scores of

LAT1 inhibitors highly correlated with their

own in vitro predicted pIC₅₀values (Supp.

Data S6). Thus, selecting the London dG

algorithm for docking could be presumed as

a closer mathematical approximation to the

real LAT1 inhibition. The current approach

has been proposed [33] and previously used

to compare different molecular docking

software and their unique algorithm [34].

the clinical translation of new theranostic

drug candidates. For example, in case of

DOTA-conjugated peptide SSTR antagonists,

⁶⁸Ga radiolabeling reduced the binding

affinity, while ¹⁷⁷Lu radiolabeling retained the

affinity similar to the native compound.

Interestingly, ⁶⁸Ga radiolabeling improved the

binding affinity of NODAGA-conjugated one

compared to the native compound [35]. In

other DOTA-peptide systems, e.g., pentixafor

scaffold or bombesin-targeting peptides, the

substitution of gallium by lutetium decreased

the binding affinity by approximately an

order of magnitude [36]. However, those

phenomena

conjugates (peptides) compared to ADPB-

based theranostic radiopharmaceutical

were

observed

in

larger

Our docking simulation showed that LAT1

designs. Whether the opposite phenomenon

applies in small molecule conjugates like

ADPB-based compounds require further

investigation.

inhibitory

potencies

of

ADPB-based

theranostic radiopharmaceuticals enhanced

when conjugated with particular radiometal-

chelating

agent

complexes.

Our

most

promising candidate compound, ¹⁷⁷Lu-DOTA-

Ahx-ADPB (predicted pIC₅₀= 51.55), exhibited

exceptionally high affinity to LAT1. Its similar

version without linker addition, ¹⁷⁷Lu-DOTA-

Ahx-ADPB, also demonstrated considerably

The observation of intermolecular interaction

showed that ¹⁷⁷Lu-DOTA-Ahx-ADPB and ¹⁷⁷Lu

DOTA-ADPB

have

their

ADPB

moeity

positioned on the upper part of the binding

pocket and have strong bonds with residues

in the unwound segment of transmembrane

6 (TM6) (Figure 5, Figure 6). Both have their

chlorine atom on dichlorophenyl moeity

interacting with the phenyl ring of proximal

high affinity (predicted pIC₅₀

=

19.42).

However, a similar result was neither

observed in the case of ⁶⁸Ga-DOTA-Ahx-

ADPB, ⁶⁸Ga-DOTA-ADPB, nor other ⁶⁸Ga-

radiolabeled

theranostic

compounds.

gating

residue

Phe252.

Their

chelate-

Therefore, we suspect that radiometal

species may significantly impact the affinity.

In light of this unexpected finding, we

overlaid the 3D binding poses based on the

same radiometal used. The overlaid image

showed a striking difference in binding poses

radiometal complexes in the deeper part of

the binding pocket possess strong hydrogen

bonds with distal gating residues Asn258 and

Tyr259. However, the higher affinity of ¹⁷⁷Lu-

DOTA-Ahx-ADPB might be contributed by: 1)

shorter intermolecular distance of hydrogen

bond between Asn258 and ¹⁷⁷Lu-DOTA-Ahx-

ADPB (2.21) than that of ¹⁷⁷Lu-DOTA-ADPB

(2.83); and 2) additional carbon-hydrogen

bond with Phe252. Previous studies showed

that strong interaction with Phe252 is one of

between

¹⁷⁷Lu-labeled

and

⁶⁸Ga-labeled

designs, almost irrespective of the carrier

molecule (data not shown). Previous studies

showed that radiometal ion has a marked

influence on the affinity of the metal

bioconjugates. However, such an effect is

unpredictable [30]. Animal studies were

performed to optimize which chelate for

which radiometal is the most appropriate for

the

key

features

Any

of

LAT1

inhibitors

toward

[18,19,21,25].

disturbance

Phe252 may cause the LAT1 to lose its 100%

transport capacity.The ADPB moeity of ⁶⁸Ga-

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H.A. Holik., et al.

Chempublish Journal, 9(2) 2025, 329-346

DOTA-Ahx-ADPB and ⁶⁸Ga-DOTA-ADPB are

positioned distal within the binding pocket

while making no significant interaction with

TM6 residues, neither did their chelate-

radiometal complex (Figure 5, Figure 6).

According to Singh et al., this pose is similar

to halogenated ligands' most favored docking

poses [19]. However, we did not observe any

strong interaction between dichlorophenyl

moieties of ⁶⁸Ga-DOTA-Ahx-ADPB nor ⁶⁸Ga-

DOTA-ADPB with their surrounding key

pocket, while ⁶⁸Ga-DOTA-Ahx-ADPB stretched

straight away beyond the upper part of the

binding pocket. ⁶⁸Ga-DOTA-Ahx-ADPB did not

exhibit a significant change of LAT1 inhibitory

potency compared to the native ADPB

(Figure 4, Supp. Data S8); however, it is

interesting to note that ⁶⁸Ga-DOTA-ADPB

whose conformation is fitted well within the

binding pocket, failed to demonstrate a

sufficient LAT1 inhibitory potency. This

finding suggests the importance of the linker

and its behavior when conjugating with a

chelating agent and radiometal [22].

amino

acid

residues.

showed that the interaction of the amino acid

moieties of LAT1 inhibitors with TM1 residues

(Gly65, Ser66, and Gly67) contributes toward

The hydrophobic effect of Ahx linker is more

pronounced when the linker is straight (as in

⁶⁸Ga-DOTA-Ahx-ADPB, Figure 6a) than in

folded state (as in ¹⁷⁷Lu-DOTA-Ahx-ADPB). In

the classic LAT1 inhibition mode, a large

hydrophobic side chain of the inhibitor

occupies the large hydrophobic pocket

surrounded by Gly255 and Trp257 in TM6

and Phe400, Trp405 and Val408 in TM10.

the

total

interaction

free

energies

[18,19,21,25]. Unlike those amino acid-based

small compounds, the amino acid moiety of

ADPB in our design is being utilized for

conjugation. Even though ⁶⁸Ga-DOTA-ADPB

has strong hydrogen bonds with Gly65,

Ser66, and Gly67, the total LAT1 inhibition

potency is the lowest among four DOTA-

conjugated ADPB-based designs. Thus, we

suspect that interaction with TM1 is not as

influential as interaction with amino acid

residues of TM6 for LAT1 inhibitory potency

However,

despite

the

hydrophobic

dichlorophenyl region of ⁶⁸Ga-DOTA-Ahx-

ADPB and ⁶⁸Ga-DOTA-ADPB satisfying that

pocket, these designs do not acquire

considerable LAT1 inhibitory potency. The

hydrophobic-hydrophilic moeity of LAT1

inhibitor has long been applied for small

molecules (L-phenylalanine and other small

substrates) [7]. Our findings suggest that

such a moiety requirement might not apply

to large conjugates. Ahx might have suitable

length and hydrophobicity for LAT1 binding

of

ADPB-based

theranostic

radiopharmaceutical designs. Even though

both TM1 and TM6 undergo conformational

change during the LAT1 transport cycle, TM6

tilts away more significantly from the binding

site and provides steric occlusion via Phe252

side chain during LAT1 transport cycle. Hence

TM6 (in particular, TM6a) is considered more

responsible for LAT1 transport [20].

pocket;

however,

fine-tuning

is

highly

recommended to obtain a better overall

design, as observed in most development

routes of theranostic radiopharmaceuticals.

It is also important to consider the LAT1-

Regarding the whole structure shape, ¹⁷⁷Lu-

DOTA-ADPB

and

⁶⁸Ga-DOTA-ADPB

are

shorter and more globular than their

counterpart version with Ahx linker. This

conformation allows both designs to fill the

binding pocket distal to the Phe252 side chain

(Figure 6a). On the other hand, ¹⁷⁷Lu-DOTA-

Ahx-ADPB and ⁶⁸Ga-DOTA-Ahx-ADPB behave

differently with their linkers. ¹⁷⁷Lu-DOTA-Ahx-

ADPB folded and flexibly fit within the binding

selectivity

of

these

LAT1-targeting

radiopharmaceutical designs. Since the final

structure is a complete departure from the

amino

acid

scaffold,

the

proposed

modifications to obtain LAT1 selectivity in

previous LAT1 inhibitor discovery might not

be applicable [7].

342

H.A. Holik., et al.

Chempublish Journal, 9(2) 2025, 329-346

To our knowledge, this is the first study to

propose a rational design of LAT1-targeting

theranostic radiopharmaceutical. The LAT1

inhibitor, chemical scaffold, and the LAT1

predicting LAT1 binding and inhibition

profiles. These results are expected to

facilitate the rational development of next-

generation

LAT1-based

therapeutic

crystal

structure

have

been

rationally

radiopharmaceuticals for various types of

cancer, with improved selectivity, efficacy,

and translational potential. The synthesis of

the designed radiotheranostic compound,

preclinical testing, and clinical testing are

research stages that can be explored further

to pave the way for the clinical use of ADPB-

selected for this particular purpose. The

actual in vitro data was employed to refine

the docking algorithm. However, this docking

study is limited because it only describes the

condition when the ligand is very close to the

receptor's binding pocket. Even though

molecular dynamic simulation may improve

the estimation, while ADMET study may

based

and

JPH203-based

radiopharmaceuticals in patients.

predict

the

in

vivo

pharmacokinetics,

however, in vitro binding and in vivo studies

in tumor xenografts will eventually provide

Acknowledgement

more

development

comprehensive

data

for

further

This research (including APC) was supported

and funded by Academic Leadership Grant

stages.

Synthesis

and

characterization of DOTA-Ahx-ADPB and

DOTA-ADPB are ongoing.

from

the

Directorate

of

Research,

Community Service, and Innovation of

Universitas Padjadjaran on behalf of A.H.S.K.,

grant number 2203/UN6.3.1/PT.00/2022. The

funders had no role in the design of the

Conclusions

In this study, we have developed a protocol

for molecular docking simulation to evaluate

the LAT1 inhibitory potency of LAT1 inhibitor-

study;

in

the

collection,

analyses,

or

interpretation of data; in the writing of the

manuscript, or in the decision to publish the

results.

based

theranostic

radiopharmaceutical

design comprised of the commercially

available theranostic chemical scaffolds and

a potent LAT1 inhibitor. The results of

molecular docking simulations using MOE for

Author Contributions

Conceptualization,

A.A.

and

H.A.H.;

various

designed

radiotheranostic

methodology, A.A., H.A.H., F.I.M., and B.S.A.S.;

software, B.S.A.S.; validation, A.A. and F.I.M.;

formal analysis, A.A. and F.I.M.; investigation,

F.I.M., J.S., and A.A.E.; resources, H.A.H. and

B.S.A.S.; data curation, A.A.; writing—original

draft preparation, A.A.; writing—review and

editing, A.A., F.I.M., H.A.H, and A.H.S.K.;

complexes demonstrate the ability of ADPB-

based and JPH203-based radiotheranostic

conjugates with radionuclides ¹¹⁷Lu and ⁶⁸Ga

to inhibit LAT1 activity in cancer cells with

good binding affinity and estimated pIC50

values. Furthermore, the intermolecular

interactions

between

these

visualization,

A.A.,

F.I.M.,

and

A.A.E;

radiopharmaceutical designs and the amino

acid residues in the binding pocket could

supervision, B.S.A.S.; project administration,

A.H.S.K.; funding acquisition, A.H.S.K.. All

authors have read and agreed to the

published version of the manuscript.

explain

each

design's

strengths

and

weaknesses. In conclusion, our approach

represents the first in silico evaluation of

therapeutic radiopharmaceuticals targeting

LAT1, providing a rational framework for

Conflict of Interest

The authors declare no conflict of interest.

343

H.A. Holik., et al.

Chempublish Journal, 9(2) 2025, 329-346

cancer diagnosis and therapeutics.

Ethical Standards

Pharmacology

107964.

10.1016/j.pharmthera.2021.10796

&

therapeutics

doi:

2021;

DOI:

This article does not contain any studies

involving human or animal subjects.

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journal of molecular sciences 2020;

21:DOI: 10.3390/ijms21176156.

[9]. Lopes C, Pereira C, Medeiros R. ASCT2

and LAT1 Contribution to the Hallmarks

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