# Core Flipping in Lead Optimization: Rank Ordering Using λ‑Dynamics

## TL;DR

This paper introduces a new computational method to determine the best binding orientation of drug molecules to their targets, improving drug design accuracy.

## Contribution

A novel λ-dynamics-based methodology is introduced to rank ligand binding poses with improved accuracy and applicability.

## Key findings

- The proposed λ-dynamics method correctly ranks X-ray poses over flipped alternatives for two drug targets.
- The method outperforms FEP/MBAR in terms of uncertainty but faces convergence challenges.
- The approach is extensible to evaluate multiple poses and amino acid rotamers.

## Abstract

In structure-based drug discovery, reliable structural
models of
ligands bound to their target receptors are critical for establishing
the structure–activity relationship of the congeneric series.
In such a series, substitutions on a common scaffold core might lead
to different binding modes, ranging from slight changes of orientations
to flipping or inversion of the core structure. Moreover, molecular
docking might lead to alternative orientations within the top-ranked
poses without being able to discriminate which is most likely. To
determine the relative binding affinities between two alternative
ligand poses, we propose a methodology based on relative binding free
energy calculations using the λ-dynamics method. We used a dual-topology
approach with distance-restraining schemes. We introduced a novel
strategy using a one-step perturbation to calculate the contributions
of the applied restraints. While using FEP/MBAR instead for that purpose
led to smaller uncertainties, it suffered from convergence issues.
We tested the validity and predictive power of our approach using
two pharmaceutically relevant targets and eight small-molecule inhibitors
from the experimentally characterized congeneric series. For each
target, our approach correctly ranks the known X-ray poses as more
favorable than alternative flipped poses. The proposed methodology
can be easily extended to rank more than two poses and should also
be applicable to the evaluation of alternative rotamers of target
amino acids.