2017
DOI: 10.1021/acs.jctc.6b01141
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Acylguanidine Beta Secretase 1 Inhibitors: A Combined Experimental and Free Energy Perturbation Study

Abstract: 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… Show more

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Cited by 81 publications
(121 citation statements)
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“…In turn, application of FEP to a vast range of protein-ligand systems revealed that the method can indeed deliver accurate relative binding affinity predictions with an error of <1 kcal mol À1 with respect to experiment. [23][24][25][26][27][28][29][30][31][32][33][34][35][36] However, the application of FEP using most MD soware remains challenging, preventing its widescale uptake.…”
Section: Introductionmentioning
confidence: 99%
“…In turn, application of FEP to a vast range of protein-ligand systems revealed that the method can indeed deliver accurate relative binding affinity predictions with an error of <1 kcal mol À1 with respect to experiment. [23][24][25][26][27][28][29][30][31][32][33][34][35][36] However, the application of FEP using most MD soware remains challenging, preventing its widescale uptake.…”
Section: Introductionmentioning
confidence: 99%
“…Similarly, moving from 1D/2D to 3D‐field descriptors also was not instrumental in the development of a better model but does suggest that the latter is quite useful in gaining good insight into the nature of substituent modification required at different regions of the scaffold. This is advantageous when considering the computational cost, time, and substituent restrictions required to achieve comparable outcomes using FEP methods for h BACE‐1 inhibitors adding immense value to the day‐to‐day medicinal chemistry design in lead optimization. Likewise, models developed using either moe or canvas descriptors achieve comparable performances suggesting that both tools capture the information content needed to build predictive models.…”
Section: Discussionmentioning
confidence: 99%
“…247,248 Binding free energy calculations (ie, an average over the ensemble binding energies) is another way to find the binding affinity. 249 Particularly, free energy perturbation (FEP) calculations was used in the design of novel spiroaminodihydropyrroles, 250 and acyl guanidine with a modified scaffold, 251 for inhibitors binding the P3 pocket of BACE1.…”
Section: Quantum Mechanical Calculationmentioning
confidence: 99%