Application of Free Energy Perturbation for the Design of BACE1 Inhibitors

Novel spiroaminodihydropyrroles probing for optimized interactions at the P3 pocket of β-secretase 1 (BACE1) were designed with the use of free energy perturbation (FEP) calculations. The resulting molecules showed pIC₅₀ potencies in enzymatic BACE1 inhibition assays ranging from approximately 5 to 7. Good correlation was observed between the predicted activity from the FEP calculations and experimental activity. Simulations run with a default 5 ns approach delivered a mean unsigned error (MUE) between prediction and experiment of 0.58 and 0.91 kcal/mol for retrospective and prospective applications, respectively. With longer simulations of 10 and 20 ns, the MUE was in both cases 0.57 kcal/mol for the retrospective application, and 0.69 and 0.59 kcal/mol for the prospective application. Other considerations that impact the quality of the calculations are discussed. This work provides an example of the value of FEP as a computational tool for drug discovery

Application of Free Energy Perturbation for the Design of BACE1 Inhibitors

Novel spiroaminodihydropyrroles probing for optimized interactions at the P3 pocket of β-secretase 1 (BACE1) were designed with the use of free energy perturbation (FEP) calculations. The resulting molecules showed pIC₅₀ potencies in enzymatic BACE1 inhibition assays ranging from approximately 5 to 7. Good correlation was observed between the predicted activity from the FEP calculations and experimental activity. Simulations run with a default 5 ns approach delivered a mean unsigned error (MUE) between prediction and experiment of 0.58 and 0.91 kcal/mol for retrospective and prospective applications, respectively. With longer simulations of 10 and 20 ns, the MUE was in both cases 0.57 kcal/mol for the retrospective application, and 0.69 and 0.59 kcal/mol for the prospective application. Other considerations that impact the quality of the calculations are discussed. This work provides an example of the value of FEP as a computational tool for drug discovery

Continuous Flow α‑Arylation of <i>N</i>,<i>N</i>‑Dialkylhydrazones under Visible-Light Photoredox Catalysis

The first direct α-arylation of aldehyde-derived <i>N</i>,<i>N</i>-dialkylhydrazones with electron deficient aryl and heteroaryl cyanides under visible-light photoredox catalysis has been developed. Structurally complex α,α′-diaryl-<i>N</i>,<i>N</i>-cycloalkylhydrazones were obtained in moderate yields by repetition of the direct arylation protocol. A continuous-flow procedure for the preparation of α-aryl-<i>N</i>,<i>N</i>-dialkylhydrazones on a multigram scale has also been established

Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study

A series of acylguanidine beta secretase 1 (BACE1) inhibitors with modified scaffold and P3 pocket substituent was synthesized and studied with free energy perturbation (FEP) calculations. The resulting molecules showed potencies in enzymatic BACE1 inhibition assays up to 1 nM. The correlation between the predicted activity from the FEP calculations and the experimental activity was good for the P3 pocket substituents. The average mean unsigned error (MUE) between prediction and experiment was 0.68 ± 0.17 kcal/mol for the default 5 ns lambda window simulation time improving to 0.35 ± 0.13 kcal/mol for 40 ns. FEP calculations for the P2′ pocket substituents on the same acylguanidine scaffold also showed good agreement with experiment and the results remained stable with repeated simulations and increased simulation time. It proved more difficult to use FEP calculations to study the scaffold modification from increasing 5 to 6 and 7 membered-rings. Although prediction and experiment were in agreement for short 2 ns simulations, as the simulation time increased the results diverged. This was improved by the use of a newly developed “Core Hopping FEP+” approach, which also showed improved stability in repeat calculations. The origins of these differences along with the value of repeat and longer simulation times are discussed. This work provides a further example of the use of FEP as a computational tool for molecular design

Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia.

We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo­[1,2-<i>a</i>]­pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound <b>25a</b> for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure–activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead <b>25a</b> are described