Introduction

MD Affinity Floes

MD affinity Floes are for running MD simulations useful for drug discovery.

New Protocol of the MD Stage in Lead Optimization

In the classic structure-based lead optimization (left in Figure New Protocol of the MD Stage in Lead Optimization), we’ve proposed the two MD stages at the bottom of the funnel: the light and fast MD screening stage, and the computationally more intense free energy calculation stage.

The Floes in the package for each MD stage are:

1. Light, fast MD screening

   1. Short Trajectory MD with Analysis Floe with 2 ns of the bound state production time

2. Relative binding free energy (RBFE)

   1. Ligand Bound and Unbound Equilibration for NES Floe

   2. Edge Mapper for RBFE calculations Floe

   3. Non-Equilibrium Switching Floe

You can use Equilibration and Non Equilibrium Switching Floe, which is the combined Floe of Ligand Bound and Unbound Equilibration for NES and Non-Equilibrium Switching Floes.

Or, you can simply combine the two MD stages and run

1. Short Trajectory MD with Analysis Floe with 6 ns of the bound state production time

2. Edge Mapper for RBFE calculations Floe

3. Non-Equilibrium Switching Floe

To get the information on the other Floes in the package, please refer to MDOrion Floes - Documentation in the left panel.

Induced-Fit Posing (Confined) Floe

In hit-to-lead (H2L), where hits from screening are assessed and processed through limited optimization to identify propitious lead compounds, knowing how hits bind to the binding site of the target can offer useful guidance in selecting promising leads. However, predicting the binding pose of hits can be challenging, especially when the hit list contains high chemical diversity, and requires an induced change in the binding site residue side chains.

Induced-Fit Posing (Confined), a new pose prediction tool for the H2L stage of drug discovery, is a 3-step protocol for the correct prediction of the binding pose of a ligand which requires induced-fit of receptor binding site residue side chains. (We refer to the induced-fit process as confined due to its limited scope.)