Optimization of kinetic stabilizers of tetrameric transthyretin: A prospective ligand efficiency-guided approach. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Cotrina, Ellen Y.; Blasi, Daniel; Vilà, Marta; Planas, Antoni; Abad-Zapatero, Cele; Centeno, Nuria B.; Quintana, Jordi; Arsequell, Gemma
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: Transthyretin -- Iododiflunisal -- TTR tetramer stabilizer -- Inhibitors -- Protein–ligand interactions -- Ligand efficiency indices (LEI) -- LEI-based approach -- Drug discovery; H-β-Ala-OMe.HCl β-alanine methyl ester -- B2Pin2 Bis(pinacolato)diboron or 4, 4, 4′, 4′, 5, 5, 5′, 5′-octamethyl-2, 2′-bi-1, 3, 2-dioxaborolane -- B(OMe)3 Trimethyl borate -- DCC N, N′-dicyclohexylcarbodiimide, IPy2BF4, bis(pyridine)iodonium tetrafluoroborate -- NCS N-chlorosuccimide -- DIPEA N, N-diisopropylethylamine -- DMSO dimethylsulfoxide -- EtAcO ethyl acetate -- HOBt 1-hydroxybenzotriazol -- HRMS high-resolution mass spectrometry -- HPLC high performance liquid chromatography -- 1H NMR proton nuclear magnetic resonance -- rt room temperature -- RT retention time -- TBAI Tetrabutyl ammonium iodide -- Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) -- tBuONO tert-butyl nitrite -- (Pd2(dba)3) Tris(dibenzylideneacetone)dipalladium(0) -- XPhos 2-Dicyclohexylphosphino-2′, 4′, 6′-triisopropylbiphenyl; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115794
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Ligand efficiency indices (LEIs) were applied prospectively for the first time to select a set of biphenyl derivatives as transthyretin inhibitors by virtual screening and docking. Some computationally prioritized compounds were synthesized and further assayed using a kinetic turbidity assay leading to a group of 3 optimized compounds. Abstract: In the past few years, attempts have been made to use decision criteria beyond Lipinski's guidelines (Rule of five) to guide drug discovery projects more effectively. Several variables and formulations have been proposed and investigated within the framework of multiparameter optimization methods to guide drug discovery. In this context, the combination of Ligand Efficiency Indices (LEI) has been predominantly used to map and monitor the drug discovery process in a retrospective fashion. Here we provide an example of the use of a novel application of the LEI methodology for prospective lead optimization by using the transthyretin (TTR) fibrillogenesis inhibitor iododiflunisal (IDIF) as example. Using this approach, a number of compounds with theoretical efficiencies higher than the reference compound IDIF were identified. From this group, ten compounds were selected, synthesized and biologically tested. Half of the compounds (5, 6, 7, 8 and 10 ) showed potencies in terms of IC50 inhibition of TTR aggregation equal or higher than the lead compound. These optimized compounds mapped within the region of more efficient candidates in the corresponding experimental nBEI-NSEI plot, matching their position in the theoretical optimization plane that was used for the prediction. Due to their upstream (North-Eastern) position in the progression lines of NPOL = 3 or 4 of the nBEI-NSEI plot, three of them (5, 6 and 8 ) are more interesting candidates than iododiflunisal because they have been optimized in the three crucial LEI variables of potency, size and polarity at the same time. This is the first example of the effectiveness of using the combined LEIs within the decision process to validate the application of the LEI formulation for the prospective optimization of lead compounds.