Exploring the Chemical Space of Multitarget Ligands Using Aligned Self-Organizing Maps

Abstract

Design of multitarget drugs and polypharmacological compounds has become popular during the past decade. However, the main approach to design such compounds is to link two selective ligands via a flexible linker. Although such chimeric ligands often have reasonable potency in vitro, the in vivo efficacy is low due to high molecular weight, low ligand efficiency, and poor pharmacokinetic profile. We developed an unprecedented in silico approach for fragment-based design of multitarget ligands. It relies on superposition of the chemical spaces related to the affinity on single targets represented by selforganizing maps. We used this approach for screening of molecular fragments, which bind to the enzymes 5-lipoxygenase (5-LO) and soluble epoxide hydrolase (sEH). Using STD-NMR and activity-based assays, we were able to identify fragments binding to both targets. Furthermore, we were able to expand one of the fragments to a potent dual inhibitor bearing a reasonable molecular weight (MW = 446) and high affinity to both targets (IC 50 of 0.03 μM toward 5-LO and 0.17 μM toward sEH).

N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells

“…Based on the chemical knowledge of the ligands and/or their targets, it is possible to design molecules from combining different pharmacophores able to reach different sites of the same protein or distinct proteins (bi-target or multi-target compounds), which could improve the anti-proliferative effect in situ, and consequently, in the improvement of the treatment efficiency 36 .…”

Fragment Screening of Soluble Epoxide Hydrolase for Lead Generation—Structure‐Based Hit Evaluation and Chemistry Exploration

“…After the closing phase of this project, 2‐phenylbenzimidazole and related derivatives were reported as fragment hits for sEH on the basis of elaborate in silico approaches . Whereas the best 2‐phenylbenzimidazole compound from those in silico screenings has a potency in the low micromolar range, compound 16 as a representative of our 2‐phenylbenzimidazole‐4‐sulfonamides has significantly higher potency (IC 50 =17 n m ).…”

“…After the closing phase of this project, 2-phenylbenzimidazole and relatedd erivatives were reported as fragment hits for sEH on the basis of elaborate in silico approaches. [27,43] Whereas the best 2-phenylbenzimidazole compound from those in silico screenings has ap otency in the low micromolar range, compound 16 as ar epresentative of our 2-phenylbenzimidazole-4sulfonamides has significantly higher potency( IC 50 = 17 nm). More importantly,t he induced-fit features associated with the 2-phenylbenzimidazole-4-sulfonamide scaffolda sr evealed by high-resolution crystal structures present distinct novel interactions with sEH.…”

“…Recently, various computational approaches have been employed in silico VS for fragment screening to find sEH inhibitors. In particular, a number of recent papers have illustrated how sophisticated computational regimes can be applied to sEH to enable efficient in silico fragment screening, for which a number of novel scaffolds have been identified that are distinct from the general amide and urea derivatives . Notably, in the in silico VS performed by Moser et al., the enforced filters included one to satisfy H‐bonding interactions to the active‐site triad as an essential pharmacophore.…”

“…In particular,anumber of recent papers have illustrated how sophisticated computational regimes can be appliedt os EH to enable efficient in silico fragment screening, for which an umber of novel scaffolds have been identified that are distinct from the general amide and urea derivatives. [27,28] Notably,i nt he in silico VS performed by Moser et al, [28] the enforced filters included one to satisfy Hbondingi nteractionst ot he active-site triad as an essential pharmacophore. Furthermore, in most of the structure-based VS procedures, the active-site pocket of sEH was treated or implied as conformationally rigid.…”