Design and Evaluation of Fragment-Like Estrogen Receptor Tetrahydroisoquinoline Ligands from a Scaffold-Detection Approach

Abstract

A library of small tetrahydroisoquinoline ligands, previously identified via structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements, has been generated as novel estrogen receptor agonistic fragments via traditional medicinal chemistry exploration. The approach described has allowed for the rapid evaluation of a structure-activity relationship of the ligands concerning estrogen receptor affinity and estrogen receptor β subtype selectivity. The structural biological insights obtained from the fragments aid the understanding of larger analogues and constitute attractive starting points for further optimization.

Thermodynamics calculation of protein–ligand interactions by QM/MM polarizable charge parameters

“…As shown in Figure 4(A) and (B), the calculated binding free energy differences between ERβ-LBD19 system to ERβ-LBD19H, ERβ-LBD8, ERβ-LBD9, or ERβ-LBD10 systems are −.13, .55, 2.03, and .95 kcal/mol under AMBER ff03 charge. However, the same binding free energy differences calculated under QMPC are about −3.49, −.08, −2.28, and −.21 kcal/mol, which are much closer to the corresponding experimental values (−2.09, −.02, −3.54, and −1.10 kcal/mol) (Möcklinghoff et al, 2011). As a result, the calculated binding free energy difference (between ERβ-LBD19 system to all ligandbound ERβ systems) under QMPC (R 2 = .61) has better correlation with the experimentally measured data than that calculated under AMBER ff03 charge parameters (R 2 = .42).…”

“…In the present study, MD simulation and MM/ GBSA calculation were performed on the systems of ERβ bound with these five ligands to understand the detailed mechanism underlying the difference in binding affinity induced by the seemingly trivial change in the ligand structure. For example, the slight change in LBD19H by replacing methyl group with a trifluoromethyl group (LBD19) was observed to increase the binding ability to ERβ about 33-fold (Möcklinghoff et al, 2011). The special nature of fluorine (high electronegativity and small size) imparts a variety of properties to certain medicines, including enhanced binding interactions, metabolic stability, changes in physical properties, and selective reactivities (Hagmann, 2008).…”

“…For ERβ protein, all ligands under study could form hydrogen bonds with the residues of R346 and E305, playing a very important role in the binding. Previous experiments showed that the LBD19 analogues lacking hydrogen bonding ability lose their binding activity (Möcklinghoff et al, 2011). Figure 7 shows the time evolution of the lengths of the two hydrogen bonds between the ligands (LBD19, LBD19H, LBD8, LBD9, and LBD10) and protein residues (R346 and E305).…”

“…The ER protein bound with either LBD19, LBD8, or LBD10 ligand was obtained from PDB entry 3OMQ, 3OMO, and 3OMP, respectively (Möcklinghoff et al, 2011). The structure of LBD19H ligand was obtained by substituting the fluorine atoms of LBD19 with hydrogen and the structure of LBD9 ligand was obtained by substituting the hydroxyl group of LBD8 with methoxyl group.…”

Novel EPHB4 Receptor Tyrosine Kinase Mutations and Kinomic Pathway Analysis in Lung Cancer

“…The PamGene platform has been used frequently and in various iterations to demonstrate gene expression 41 , biochemical mechanisms 42 , rational personalized therapy selection and design [43][44][45] , drug target discovery 46,47 , and microbe species detection and identification 48,49 . Many of these studies have involved cancer signaling, treatment, and target identification and characterization.…”