Fragment-based design of selective GPCR ligands guided by free energy simulations

Abstract

Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Herein, we explored strategies for structure-based evolution of fragments binding to a G protein-coupled receptor....

Dual A1/A3 Adenosine Receptor Antagonists: Binding Kinetics and Structure−Activity Relationship Studies Using Mutagenesis and Alchemical Binding Free Energy Calculations

“…FEP/MD 48,75−82 simulations have been applied for ligand optimization in class A GPCRs including ARs. 75−82 Thus, FEP/MD calculations have been applied for lead fragment or lead compound optimization against the A 2A R 75,77 or for SAR interpretation, for example, 3deazaadenosine agonists against A 2A R 81 and thiazolo [5,4d]pirimidines ligands against A 2A R. 82 We performed TI/MD calculations for nine alchemical transformations of the ligand complexes with A 1 R, as listed in Table 4. The set of the studied compounds A15, L2−L6, L8, and L9 cover ∼100 units of pK d s range.…”

Molecular Simulations and Drug Discovery of Adenosine Receptors

“…Compared with MM/PBSA or MM/GBSA, MD/FEP is a more accurate binding free energy calculation method. Therefore, MD/FEP has been routinely used in drug design projects [ 45 , 145 , 148 , 149 , 150 , 151 , 152 ]. For the A 2A AR, MD/FEP calculations suggested the loss of binding of 3-deazaadenosine due to modification of a single heavy atom in ADO [ 150 ].…”

“…MD/FEP has been widely applied in the fragment-to-lead optimization process. Matricon et al [ 149 ] discovered that the benzothiazole fragment bound to the A 1 AR through hydrogen bond interactions with N 6.55 . Through a single vector growth, they designed nine additional compounds from the initial fragment, all of which showed improved binding affinity as suggested by MD/FEP calculations [ 149 ].…”

“…Matricon et al [ 149 ] discovered that the benzothiazole fragment bound to the A 1 AR through hydrogen bond interactions with N 6.55 . Through a single vector growth, they designed nine additional compounds from the initial fragment, all of which showed improved binding affinity as suggested by MD/FEP calculations [ 149 ]. Eventually, the compounds were synthesized and their binding affinities in the A 1 AR were experimentally measured by radioligand binding assays [ 149 ].…”

“…Through a single vector growth, they designed nine additional compounds from the initial fragment, all of which showed improved binding affinity as suggested by MD/FEP calculations [ 149 ]. Eventually, the compounds were synthesized and their binding affinities in the A 1 AR were experimentally measured by radioligand binding assays [ 149 ]. The resulting ligands led to >1000-fold improvements of binding affinity and nearly 40-fold higher subtype selectivity.…”