Lysine-Specific Demethylase 1 Inhibitors: A Comprehensive Review Utilizing Computer-Aided Drug Design Technologies

Abstract

Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising therapeutic target for treating various cancers (such as breast cancer, liver cancer, etc.) and other diseases (blood diseases, cardiovascular diseases, etc.), owing to its observed overexpression, thereby presenting significant opportunities in drug development. Since its discovery in 2004, extensive research has been conducted on LSD1 inhibitors, with notable contributions from computational approaches. This review systematically summarizes LSD1 inhibitors investigated through computer-aided drug design (CADD) technologies since 2010, showcasing a diverse range of chemical scaffolds, including phenelzine derivatives, tranylcypromine (abbreviated as TCP or 2-PCPA) derivatives, nitrogen-containing heterocyclic (pyridine, pyrimidine, azole, thieno[3,2-b]pyrrole, indole, quinoline and benzoxazole) derivatives, natural products (including sanguinarine, phenolic compounds and resveratrol derivatives, flavonoids and other natural products) and others (including thiourea compounds, Fenoldopam and Raloxifene, (4-cyanophenyl)glycine derivatives, propargylamine and benzohydrazide derivatives and inhibitors discovered through AI techniques). Computational techniques, such as virtual screening, molecular docking and 3D-QSAR models, have played a pivotal role in elucidating the interactions between these inhibitors and LSD1. Moreover, the integration of cutting-edge technologies such as artificial intelligence holds promise in facilitating the discovery of novel LSD1 inhibitors. The comprehensive insights presented in this review aim to provide valuable information for advancing further research on LSD1 inhibitors.

Keywords: LSD1/KDM1A inhibitor; QSAR; computer-aided drug design; molecular docking; molecular dynamics simulation.

Figure 1

The structure of LSD1 (PDB code: 6TUY) composed of three major domains, namely the N-terminal SWIRM domain (green), Tower domain (pink) and the C-terminal amino oxidase-like (AOL) domain (cyan).

Figure 2

The structures of phenelzine derivatives. (A) Compound 1; K_i(inact) is the apparent maximum inactivation rate. (B) Compound 2 and the binding mode with LSD1; the key amino acids are illustrated, and orange dash lines represent the hydrogen bond interactions (Reprinted with permission from Ref. [40]. Copyright 2015 Taylor & Francis). (C) Compound 3 and compound 4; IC₅₀ is half maximal inhibitory concentration.

Figure 3

The structures of tranylcypromine derivatives. (A) Compounds 5 and 6; (B) the co-crystal structural comparison of MAO-B/compound 5 complex and LSD1/compound 5 complex (reprinted with permission from Ref. [50] Copyright 2010 American Chemical Society); (C) Compound 7 and the 2-PCPA benzene ring formed stable hydrophobic interactions with the surrounding residues (reprinted with permission from Ref. [50] Copyright 2010 American Chemical Society); (D) compound 8 and predicted binding model of compound 8 with LSD1 (reprinted with permission from Ref. [51]. Copyright 2017 Elsevier); (E) compound 9 and complex structure of LSD1 upon binding to compound 9 (reprinted with permission from Ref. [52]. Copyright 2022 American Chemical Society).

Figure 4

The structures of pyridine derivatives. (A) Compound 10 (GSK-690) and compound 11; (B) complex structure of LSD1 upon binding to compound 11 ((left), PDB code: 2V1D, reprinted with permission from Ref. [55]. Copyright 2016 American Chemical Society) and superposition of molecular docking result with the average structure during MD of compound 11 ((right), reprinted with permission from Ref. [56]. Copyright 2018 Taylor & Francis); (C) compounds 12–16.

Figure 5

The structure of pyrimidine derivatives. (A) Compound 17 (left), the docking result ((middle), PDB code: 2H94) and the binding mode of compound 17 with LSD1 after MD simulation ((right), reprinted with permission from Ref. [64]. Copyright 2017 Elsevier); (B) compound 18 (Osimertinib) and compound 19, and the binding mode of compound 19 with LSD1 (right, green dash lines represent the hydrogen bond interactions, yellow dash line is π–π stacking, reprinted with permission from Ref. [66]. Copyright 2022 Elsevier); (C) the structures of compound 20 and compound 21; (D) the docking mode of compound 20 with LSD1 (adapted from Ref. [67]); (E) the co-crystal structure of compound 21 in complex with LSD1 (PDB code: 6W4K, reprinted from Ref. [67]).

Figure 6

The structures of triazole derivatives (A) compounds 22 and 23; (B) two conformations of triazole derivatives at the binding site (type A, the triazole moiety in close proximity to pocket 1, (left); type B, the triazole moiety in close proximity to pocket 2, (right), reprinted with permission from Ref. [73]. Copyright 2018 Royal Society of Chemistry); (C) compounds 24–27.

Figure 7

The structures of triazole derivatives. (A) Compounds 28 and 29. (B) Complex structure of LSD1 upon binding to compound 28 (PDB code: 3ZMT, reprinted with permission from Ref. [79]. Copyright 2018 Royal Society of Chemistry); the key amino acids are illustrated. (C) Compounds 30 and 31; (D) 2D diagram of the interaction between compound 30 and LSD1 (reprinted from Ref. [80]); (E) surface map for the compound 30 inside active site (reprinted from Ref. [80]).

Figure 8

The structures of thiazole derivatives, compounds 32–36.

Figure 9

The structures of thiazole derivatives. (A) Compounds 37–42; (B) compound 40 bound inside the active site of LSD1; yellow dotted line represents electrostatic interactions; pink dotted lines are π–π stacking (reprinted with permission from Ref. [82]. Copyright 2019 Elsevier).

Figure 10

The structures of pyrazole derivatives. (A) Compounds 43 and 44; (B) compound 45, along with a 2D diagram depicting its interaction with LSD1 (reprinted with permission from Ref. [85]. Copyright 2019 Elsevier); (C) compounds 46 and 47.

Figure 11

The structures of thieno[3,2-b]pyrrole derivatives, compounds 48–52.

Figure 12

The superposition of the docking structures (green) and MD average structures (cyan) of LSD1 with (A) compound 53, (B) compound 54 and (C) compound 55, respectively (reprinted from Ref. [88]).

Figure 13

The structures of indole derivatives. (A) Compounds 56 and 57; (B) complex structure of LSD1 upon binding to compound 57; the key residues are labeled (reprinted with permission from Ref. [94]. Copyright 2018 Elsevier). (C) Compound 57 in the pocket cavity of LSD1 (reprinted with permission from Ref. [94]. Copyright 2018 Elsevier). (D) Compounds 58 and 59; (E) compounds 60 and 61; (F) complex structure of LSD1 upon binding to compound 61 (PDB code: 5YJB); green dash lines represent hydrogen bond interactions; yellow dash lines are π–π stacking (reprinted with permission from Ref. [96]. Copyright 2022 Elsevier).

Figure 14

The structures and binding mode analysis of quinoline derivatives. (A) Binding mode of LSD1 with compound 62 (reprinted with permission from Ref. [97]. Copyright 2020 Elsevier); (B) binding mode of LSD1 with compound 63 (reprinted with permission from Ref. [97]. Copyright 2020 Elsevier); (C) compound 63 and compound 64; (D) compound 62 and design and modification strategy of the target compound; (E) the proposed binding mode of LSD1 with compound 65 (reprinted with permission from Ref. [98]. Copyright 2021 John Wiley and Sons); (F) the proposed binding mode of LSD1 with compound 72 (reprinted with permission from Ref. [98]. Copyright 2021 John Wiley and Sons); (G) compounds 65–72.

Figure 15

(A) The structures of phenyloxazole derivatives compounds 73–75; (B) binding orientation and (C) 2D diagram of interactions of compound 75 at the LSD1 binding site (reprinted with permission from Ref. [99]. Copyright 2013 Royal Society of Chemistry).

Figure 16

(A) The structure of compound 76 (Sanguinarine) and Epiberberine; (B) predicted binding mode of compound 76 in the active site of LSD1 (PDB: 2V1D, reprinted from Ref. [100]); (C) overlap of the binding poses of compound 76, Epiberberine and FAD (reprinted from Ref. [100]).

Figure 17

(A) The structures of phenolic compounds of compounds 77–84; (B) complex structure of LSD1 upon binding to compound 77 (PDB: 2IW5, reprinted from Ref. [110]).

Figure 18

(A) The structures of resveratrol derivatives: compounds 85–87; (B) complex structure of LSD1 upon binding to compound 85; key amino acid residues and interactions are indicated (reprinted with permission from Ref. [113]. Copyright 2017 Elsevier); (C) Docking diagram of compound 87 with LSD1 (left) and 2D schematics of the protein–ligand interactions of compound 87 to LSD1 (right) (reprinted with permission from Ref. [114]. Copyright 2018 Elsevier).

Figure 19

(A) 3D-QSAR contour maps visualize the effect of the introduced substituents on the biological activity (reprinted with permission from Ref. [102]); (B) structure–activity relationship (reprinted with permission from Ref. [102]); (C) the structures of resveratrol derivatives: compounds 88–93.

Figure 20

The structures and of flavonoids inhibitors. (A) Compounds 94 (Baicalin) and 95 (Wogonoside); (B) 3D docking model of compound 95 bound to LSD1(reprinted with permission from Ref. [123]. Copyright 2018 Elsevier); (C) 2D schematic of the docking model of compound 95 bound to LSD1(reprinted with permission from Ref. [123]. Copyright 2018 Elsevier); (D) compound 96 (IQ) and (E) 2D schematic of the docking model bound to LSD1(reprinted with permission from Ref. [124]. Copyright 2019 Elsevier).

Figure 21

The structures of natural-product compounds 97–100.

Figure 22

The structures of thiourea compounds. (A) Compounds 101–104; (B) computer-predicted binding mode of compounds 104 and 106 in the LSD1 binding site (left), molecular interactions between LSD1 and compound 104 (right) (reprinted with permission from Ref. [128]. Copyright 2015 Elsevier); (C) compounds 105 and 106.

Figure 23

(A) The structures of compounds 107 (Fenoldopam) and 108 (Raloxifene); molecular docking results of (B) compounds 107 (reprinted with permission from Ref. [130]. Copyright 2021 Elsevier) and (C) 108 bonding to LSD1; hydrogen bonds and their distances are shown (reprinted from Ref. [131]). (D) Compounds 107 (reprinted with permission from Ref. [130]. Copyright 2021 Elsevier) and (E) 108 were buried in a hydrophobic pocket of LSD1 (reprinted from Ref. [131]); (F) 2D diagram depicting their interaction (up, compounds 107 reprinted with permission from Ref. [130]. Copyright 2021 Elsevier and 108, down, reprinted from Ref. [131]) with LSD1.

Figure 24

The structures of (4-cyanophenyl)glycine derivatives. (A) Compounds 109 and 110; (B) 2D diagram depicting interaction of compound 109 with LSD1 (reprinted with permission from Ref. [132]. Copyright 2017 American Chemical Society); (C) compounds 111–114.

Figure 25

The proposed binding modes of LSD1 with compounds (A) 111, (B) 112, (C) 113 and (D) 114, respectively (reprinted with permission from Ref. [133]. Copyright 2019 Elsevier).

Figure 26

(A) The structures of propargylamine derivatives: compounds 115–117; complex structure of LSD1 upon binding to (B) compounds 115 (reprinted with permission from Ref. [135]. Copyright 2013 American Chemical Society) and (C) 116 (reprinted with permission from Ref. [135]. Copyright 2013 American Chemical Society).

Figure 27

The structures of benzoylhydrazine derivatives. (A) Compounds 118–123; (B) compounds 124–126; (C) binding mode of compound 124 (reprinted with permission from Ref. [139]. Copyright 2016 Elsevier) and (D) compound 126 with LSD1; key residues are shown (reprinted with permission from Ref. [139]. Copyright 2016 Elsevier).

Figure 28

The structures of LSD1 inhibitors discovered through artificial intelligence techniques. (A) Compounds 127–131 (with the predicted IC₅₀); (B) compounds 132–136.