Overcoming Challenging Substituent Perturbations with Multisite λ-Dynamics: A Case Study Targeting β-Secretase 1

The Journal of Physical Chemistry Letters
Jonah Z VilseckCharles L Brooks

Abstract

Alchemical free energy calculations have made a dramatic impact upon the field of structure-based drug design by allowing functional group modifications to be explored computationally prior to experimental synthesis and assay evaluation, thereby informing and directing synthetic strategies. In furthering the advancement of this area, a series of 21 β-secretase 1 (BACE1) inhibitors developed by Janssen Pharmaceuticals were examined to evaluate the ability to explore large substituent perturbations, some of which contain scaffold modifications, with multisite λ-dynamics (MSλD), an innovative alchemical free energy framework. Our findings indicate that MSλD is able to efficiently explore all structurally diverse ligand end-states simultaneously within a single MD simulation with a high degree of precision and with reduced computational costs compared to the widely used approach TI/MBAR. Furthermore, computational predictions were shown to be accurate to within 0.5-0.8 kcal/mol when CM1A partial atomic charges were combined with CHARMM or OPLS-AA-based force fields, demonstrating that MSλD is force field independent and a viable alternative to FEP or TI approaches for drug design.

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Citations

Apr 13, 2021·Journal of Computational Chemistry·Ryan L Hayes, Charles L Brooks
Jun 9, 2021·Journal of Chemical Theory and Computation·Jonah Z VilseckCharles L Brooks
Jul 28, 2021·Nature Communications·P Takunda ChazovachiiAnne J McNeil
Nov 18, 2020·Journal of Chemical Theory and Computation·E Prabhu RamanCharles L Brooks
Oct 29, 2021·Journal of Chemical Theory and Computation·Ryan L HayesCharles L Brooks

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