Evolutions in fragment-based drug design: the deconstruction-reconstruction approach

Abstract

Recent advances in the understanding of molecular recognition and protein-ligand interactions have facilitated rapid development of potent and selective ligands for therapeutically relevant targets. Over the past two decades, a variety of useful approaches and emerging techniques have been developed to promote the identification and optimization of leads that have high potential for generating new therapeutic agents. Intriguingly, the innovation of a fragment-based drug design (FBDD) approach has enabled rapid and efficient progress in drug discovery. In this critical review, we focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening (FBS) for constructing such libraries. We also highlight the deconstruction-reconstruction strategy by utilizing privileged fragments of reported ligands.

Figure 1

(A) Schematic representation of the deconstruction–reconstruction approach in fragment-based drug design (FBDD). (B) Flow diagram of the deconstruction–reconstruction approach in FBDD. Abbreviation: ADMET, absorption, distribution, metabolism, excretion, and toxicity.

Figure 2

The discovery of orally bioavailable signal transducers and activators of transcription 3 (STAT3) inhibitor HJC0123 by utilizing a deconstruction–reconstruction approach. (A) Deconstruction of known STAT3 inhibitors to identify privileged fragments. (B) Reconstruction of novel STAT3 inhibitors. (C) The predicted binding mode of HJC0123 to the STAT3 SH2 domain. (D) In vivo efficacy of HJC0123 in inhibiting growth of xenograft tumors in mice (p.o.). Reproduced, with permission, from [49].

Figure 3

(A) The evolution of linker design and discovery of novel signal transducers and activators of transcription 3 (STAT3) inhibitor 1 via in silico site-directed fragment-based drug design (FBDD). (B) Rational design of nocaine/modafinil hybrid ligand 2 and novel triple reuptake inhibitor JZAD-IV-22 by utilizing a deconstruction–reconstruction approach. (C) A benzamide derivative 3 as the glucokinase activator was designed and assembled by using a deconstruction–reconstruction approach through a privileged fragment-merging strategy. (D) Discovery of the spirocyclic pyranopyrazole 6 as a novel sigma 1 (σ₁) receptor ligand by the combination of the privileged fragments from known σ₁ receptor ligands 4 and 5.

Figure 4

The discovery of HJC0122 and HJC0124 as new -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-positive allosteric modulators (PAMs). (A) Overlay analysis of the nine known PAMs with structures available from the Protein Data Bank (PDB). (B) General deconstruction–reconstruction approach for drug design schemes. (C) Predicted binding mode of HJC0122 (pink) to the GluA2 dimer interface. (D) Modulation of the effect of AMPA (1 MM) on caspase-3 activity induced by phencyclidine (PCP) at 3 MM in a concentration-dependent fashion and with higher potency compared with LY451395 (in Phase II clinical trials). Inset, chemical structures of neuroprotective agents HJC0122 and HJC0124. Reproduced, with permission, from [59].