jz9b02004_si_001.pdf (3.13 MB)
Overcoming Challenging Substituent Perturbations with Multisite λ‑Dynamics: A Case Study Targeting β‑Secretase 1
Version 2 2019-08-19, 19:35
Version 1 2019-08-13, 14:10
journal contribution
posted on 2019-08-19, 19:35 authored by Jonah Z. Vilseck, Noor Sohail, Ryan L. Hayes, Charles L. BrooksAlchemical
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.