Table 1 Docking energy scores and amino acids involved in the binding site for SphK inhibitors with the active site of SphK1

Lipid-like small molecules SphK inhibitors

Sphingoguanidine-based SphK

LCL351

N-[(4E)-1-hydroxyoctadec-4-en-2-yl] guanidine

− 7.7789

THR 54

SLR080811

(2S)-2-[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl] pyrrolidine-1-carboximidamide; hydrochloride

–

–

SLM6031434

(2S)-2- [3- [4- (Octyloxy)-3-(trifluoromethyl) phenyl]-1,2,4-oxadiazol-5-yl]-1-pyrrolidinecarboximidamide hydrochloride

–

–

SLC5111312

(2S,3S)-3-hydroxy-2-(3-(6- (pentyloxy) naphthalen-2-yl)-1,2,4-oxadiazol-5-yl) pyrrolidine-1-carboximidamide hydrochloride

–

–

SLP120701

(S)-2-(3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl) azetidine-1-carboximidamide hydrochloride

–

–

SLC4011540

2-(3-[4-({4-[4- (difluoro methyl) phenyl]-1,3-thiazol-2-ylamino)phenyl]-1,2,4-oxadiazol-5-yl methyl)pyrrolidine-1-carboximidamide

− 9.3994

ARG 191

GLY 342

SLP7111228

(2S)-2-[[3-(4-octylphenyl)-1,2,4-oxadiazol-5-yl] methyl] pyrrolidine-1-carboximidamide; hydrochloride

–

–

Amidine-based SphK inhibitors

VPC96091

(2S-1-(4-dodecylbenzoyl) pyrrolidine-2-carboximidamide

–

–

VPC94075

N-[(2S)-1-amino-1-iminopropan-2-yl]-4-octylbenzamide; hydrochloride

–

–

Compound 28

1-carbamimidoyl-N-(4-dodecylphenyl) cyclopropane-1-carboxamide

− 8.2461

N 44- ASP 178 &

N 56- ASP 178 &

ARG 191

Compound 1a

1-(4-dodecylbenzoyl) pyrrolidine-2-carboximidamide

− 8.0355

ASP 178

SER 168

ARG 191

Piperidine-based SphK inhibitors

Compound 82

(1–2-[4-({2-[4-(trifluoromethyl) phenyl]-1,3-thiazol-5-yl amino)phenyl]ethyl piperidin-2-yl)methanol

− 7.6419

GLY 113

ARG 185

RB-005

1-[2-(4-octylphenyl)ethyl] piperidin-4-amine

− 7.3644

GLY 113

SK1-5c

2, 2-dimethyl-4S-(1-oxo-2 hexadecyn-1-yl)-1, 1-dimethylethyl ester-3-oxazolidinecarboxylic acid

− 8.9416

GLU 343

Pyrrolidine-based SphK inhibitors

CHJ01

(2R,3S,4S)-4-amino-2-tetradecylpyrrolidin-3-ol; dihydrochloride

–

–

Compound 51

(SK1-IN-1)

(2S, 3S)-N-(S)-1-(4- (5-(2-cyclopentylethyl)-1, 2, 4-oxadiazol-3-yl) phenyl) ethyl) hydroxypyrroli-dine-2-carboxamide

− 8.0534

GLY 26

GLY 111

SER 112

PF-543

Reference molecule

[(2R)-1-[[4-[[3-(benzenesulfonylmethyl)-5-methylphenoxy] methyl] phenyl]methyl]pyrrolidin-2-yl]methanol

− 8.9563

GLY 26

SER 112

LYS 27

ARG 191

GLY 342

Naphthalene based SphK inhibitors

SLC5091592

(2S)-2-[3-[6-[[3-(trifluoromethyl) phenyl]methoxy]naphthalen-2-yl]-1,2,4-oxadiazol-5-yl]pyrrolidine-1-carboximidamide;hydrochloride

–

–

Amino alcohol-based SphK inhibitors

SK1-I

(2R, 3S, 4E)-N-methyl-5-(4-pentylphenyl)-2-aminopent-4-ene-1, 3-diol)

− 6.7484

ARG 191

GLY 342

DHS (Safingol)

[(2S,3S)-1,3-dihydroxyoctadecan-2-yl] azanium

− 6.9007

ASP 81

ASP 178

ARG 191

ASP 178

DMS

(E,2S,3R)-2-(dimethylamino) octadec-4-ene-1,3-diol

− 7.0454

GLU 182

ARG 191

K145

3-(2-amino-ethyl)-5-[3-(4-butoxyl-phenyl)-propylidene]-thiazolidine-2,4dione

− 6.7742

GLU 343

GLU 343

SG12

2-amino-4-(4-octylphenyl) butane-1,3-diol

− 6.6408

GLU 343

GLU 182

SG14

N-[2-hydroxy-1-phenyl-5-(pyrrolidin-1-yl) pentan-3-yl] octadecanamide

− 11.4135

GLY 113

Amgen 82

2-(hydroxymethyl)-1-2-[4-({4-[4-(trifluoromethyl) phenyl]-1,3-thiazol-2-yl amino) phenyl] ethyl piperidin-4-ol; trifluoromethane

− 8.2950

GLY-133 & ASP 178& GLY 82 & ILE 174

FTY720

(2-amino-2-[2-(4-octylphenyl) ethyl] propane-1, 3-diol)

− 7.1602

LEU 268

ARG 191

GLY 342

(S)-FTY720 vinyl phosphonate

[(3S)-3-amino-3-(hydroxymethyl)-5-(4-octylphenyl) pent-1-enyl]phosphonic acid

− 7.0428

GLY-111 & SER-112

ROMe (R)-FTY720-OMe)

(2R)-2-amino-2-(methoxymethyl)-4-(4-octylphenyl) butan-1-ol

− 6.8914

SER 79

GLY 82

Non-lipid like small molecule SphK inhibitors

Benzene sulfonamide-based SphKs inhibitors

MP-A08

4-Methyl-N-[2-[2-[(4-methylphenyl) sulfonyl] amino] phenyl] amino] methyl]phenyl] benzene sulfonamide

− 7.2889

GLU 182

GLY 82

SKI-II

4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl] amino]phenol

− 6.5171

ASP 178

MET 272

11b

6-(hydroxymethyl)-3-[(1E)-3-(4-[4-(naphthalen-2-yl) pyrimidin-2-yl] amino- phenyl)-3-oxoprop-1-en-1-yl]-1,2-dihydroquinolin-2-one

− 8.2255

SER 112

SKI-I

N-[(E)-(2-hydroxynaphthalen-1-yl) methylidene amino]-3-naphthalen-2-yl-1H-pyrazole-5-carboxamide

− 8.2044

SER 168

SKI-I-Asp

3-[(E)-([3-(naphthalen-2-yl)-1H-pyrazol-5-yl] formamide-amino)methyl]naphthalen-2-yl 2-(methoxy methoxy)benzoate

− 8.1246

GLY 82

ARG 191

GLY 25

SKI-178

N-[(E)-1-(3,4-dimethoxyphenyl) ethylidene amino]-3-(4-methoxyphenyl)-1H-pyrazole-5-carboxamide

− 8.8007

MET 272

SK-F

N-(4-octylphenyl) benzamide

− 7.9155

ILE 174

Opaganib ABC294640

3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl) adamantane-1-carboxamide

− 6.6796

GLY 25

ABC294735

3-(4-chlorophenyl)-N-[(3,4-dihydroxyphenyl) methyl] adamantane-1-carboxamide

− 7.3269

ASP-178

CB5468139

N-(3-chloro-1,4-dioxonaphthalen-2-yl)-N-cyclohexyl acetamide

− 6.0431

GLU 343

ST-1803

4-methyl-N-[4-(1,3-thiazol-2-yl)-1,3-thiazol-2-yl]-1,3-thiazol-2-amine

− 5.8147

ILE 174

ILE 174

SphK inhibitors from natural sources

Pachastrissamine (jaspine B)

(2S,3S,4S)-4-amino-2-tetradecyloxolan-3-ol

− 7.6449

ARG 56

GLU 55

ALA 60

F-12509a

(6aR,12aR,12bS)-10-hydroxy-4,4,6a,12b-tetramethyl-1,2,3,4a,5,6,12,12a-octahydrobenzo[a]xanthene-8,11-dione

− 5.9055

ARG 191

ARG 191

B-5354C

[(Z)-tetradec-7-enyl] 4-amino-3-hydroxybenzoate

− 8.2508

GLY 82 & PHE 192

Balanocarpol

(1R,8S,9S,16R)-8,16-bis(4-hydroxyphenyl)-15-oxatetracyclo [8.6.1.0^2,7.0^14,17] heptadeca-2(7),3,5,10(17),11,13-hexaene-4,6,9,12-tetrol

− 5.7554

ARG 57 & GLU 55 & ALA 110

Icaritin

3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl) chromen-4-one

− 6.2876

GLU 343

SER 79

ARG 185

Hispidulin

5,7-dihydroxy-2-(4-hydroxyphenyl)-6-methoxychromen-4-one

− 6.3303

MET 272

Peretinoin

(2E,4E,6E,10E)-3,7,11,15-tetramethylhexadeca-2,4,6,10,14-pentaenoic acid

− 6.6058

ARG 57

Pristimerin

methyl (2R,4aS,6aR,6aS,14aS,14bR)-10-hydroxy-2,4a,6a,6a,9,14a-hexamethyl-11-oxo-1,3,4,5,6,13,14,14b-octahydropicene-2-carboxylate

− 7.1293

GLU 182

ARG 191

ARG 191

Suramin

8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-1-yl) carbamoyl] phenyl] carbamoyl] phenyl] carbamoyl amino] benzoyl] amino] benzoyl] amino]naphthalene-1,3,5-trisulfonic acid

− 7.0881

ASP 81

MET 272

ARG 24

ARG 185

ARG 24

Ellagic acid (EA)

6,7,13,14-tetrahydroxy-2,9-dioxatetracyclo [6.6.2.0^4,16.0^11,15] hexadeca-1(15),4,6,8(16),11,13-hexaene-3,10-dione

− 4.9543

SER 79

LEU 83

GLY 113 (A)

GLY 113 (A

Epigallocatechin-3-gallate (EGCG)

[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate

− 6.9770

GLY 113

GLY 342

GLU 343