Table 2.

Inhibitors of protein targets in the insulin signaling pathways, studied via molecular docking, and their plausible binding sites.

Protein	Inhibitors found using docking experiments	Interaction used AA residues
Insulin receptor and PTP-1β	IR: herbacetin and sorbifolin [120] IR: ANP [129] PTP1β: secoisoresinol, pinoresinol, cedeodarin, and UN608 [129] PTP1B: CYC31 [109] PTP1B: carainterol A [110]	IR-PTP1β: Tyr48, and His110 [120] IR: Leu1002, Met1079, and Asp1150 [120] PTP1β: Ser1006, Lys1030, Asp1083, Met1079, and Glu1077 [129] PTP1B: Ala217, Arg221, Gly183, and Gln266 [109]
PI3K signaling proteins	PDK1-PI3K: myricetin, quercetin, morin, luteolin, and emodin [138] Akt: sulforaphane and curcumin [138] PIK3-Akt: carainterol A [110] Akt1: 6-0-feruloyl catalpol, 5,7-dihydroxy-8-(3-methyl-2-butenyl) coumarin, isobutrin, MBH-4-flouroracemic, irigenin, junipeginin C, 5,7,4′-trihydroxyflavone-3-O-glucuronide, and ovalitenone [185]. Akt1: 3,5-trisubstituted pyridines, 5-pyrrolopyridinyl-2-thiophenecarboxamides, pyrrolopyrimidine, dihydrothieno and dihydrofuropyrimidines, and isoquinoline–pyridine with oxindole–pyridine derivatives [185]. Akt1: quercetin-7-O-β-D-glucopyranoside [200]. Akt-MTOR: 6-methylheptyl sulfate, aegelinol, 2-hydroxynephthenol, iodocionin, (Z)-oct-5-enyl sulfate, osthol [53] Akt: vemurafenib [148]. MTOR: riboflavin [148]. PI3K-Akt-MTOR: wotmannin, MK-2206, LY-294002, mitoxantrone, and rapamycin [148]. Akt1: hesperetin [171]	PDK1: Leu88, Leu159, Ala109, Val143, Tyr161, Ala162, Ala162, Leu212, Ser160, Glu209, and Thr222 [138] PIK3: Pro810, Trp812, Tyr867, Ile 881, Val882, Ala885, Ile879, met 953, and Phe961 [138] Akt1: Leu156, Val164, Ala177, Met227, Tyr229, Ala230, Phe236, Phe237, Met281, Tyr437, Phe438, and Phe442; polar Thr211, Asp279, Thr291, Thr435, and Thr443 residues; negatively charged Glu228, Glu234, Glu278, Asp292, and Asp439 residues; positively charged Lys158, Lys179, and Arg241 [185]. Akt: Ala230, Glu226, Glu234, Tyr272, Val164, Ala177, Ilu800, Thr291, and Met28 [148] MTOR: Val882 and Lys890 [148]. Akt1: Gln79, Thr211, and Leu210 [171]. PI3Kα site A: Lys802, Asp810, Asp933, and Val851 [152]. PI3Kα site B: Val851 and Gln859 [152]. PI3Kγ site A: Lys833 [152]. PI3Kγ site B: Lys833 and ASP844 [152]. PI3K–C2β: Val1115 [152]. P70S6K1: Glu143 and Lys123 [152]. mTOR site A: Lys-asp pair [152] mTOR site B, backbone nucleotide loop [152]. PI3Kγ: Met804, Ser806, Trp812, Ile831, Lys833, Tyr867, Ile879, Asp950, Asn951, Met953, Ile963, and Asp964 [159]. Akt: Residues Leu156, Gly157, Val164, Ala177, Thr211, Met227, Glu228, Ala230, Glu234, Met281, Thr291, Asp292, Phe438, and Phe442 [159]. mTOR:: Leu2185, Glu2190, Asp2195, Tyr2225, Ile2237, Gly2238, Trp2239, Val2240, Met2345, Ile2356, and Asp2357 [159]. PI3K: His39, Phe87, Phe88, Phe111, Phe112, Asn114, Met115, Phe116, Tyr166, Arg170, Tyr184, Asp185, Val186, Leu187, Gln203, Leu206, Lys210, Phe211, Trp259, Gly260, Tyr262, His263, Phe265, Ser266, Leu267, Glu269, Ala270, Trp283, Leu286, Pro287, Phe288, Val289, Thr290, Ser291, Leu292, and Ala293 Phe294 [219]. Akt: Ser205 [223]
Further proteins effecting insulin signaling	RAC1: subsets of flavonoids, morpholines, and imidazoles [251] RAC1-HSP90-EGFR-CDH1-COPS2: rhein [259] SRAC1: 4F rhein derivative, NSC23766 [274]	RAC1: Asp65-arg-66-Arg68-Pro69 and Ala95-lys96-pro99-glu100-his103-his104 [251].
PTEN	Naringin [279]	Cys124, Arg130, His93, Gly127, Asp92, Gln171, Ala126, Lys125, and Lys 128 [287]. Tyr16, Asp24, Arg47, Gly44, Val45, Asp92, His93, Ala126, Lys128, Asp162, Lys164, Asp326, Lys330.Tyr16, Val45, Asp92, and Ala126 [299]. Tyr16, Val45, Ala126, and Asp92 [300].
GLUT4	Stigmasterol glucoside [301]. N-(3-(3-(4-Fluorophenyl)propyl)benzyl-3-(2-methoxyphenyl)-N-pyridin-4-ylmethyl)propanamide and (3-((3-((methyl((quinolin-6-ylmethyl)amino)methyl)phenoxy)methyl)piperidin-1-yl) (1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methanone [312]	Gln439, Ala86, Ile184, Asn431, Phe88, Ile42, Tyr308, Val85, Ala86, and Ile184 [301]. Leu185, Ile42, Phe307, Asn427, Asn176, and Trp404 [312]. Ile42, Leu185, Phe38, Phe307, Asn427, and Trp404 [312].