[ RIDE Setup | RIDE Server Setup | RIDE GPU Benchmark ]

RIDE is a fast 3D molecular similarity search method based on Atomic Property Fields, developed at MolSoft. RIDE searches databases of compound conformers for molecules that are isosteric to the query, i.e. have similar 3D configurations and distributions of atomic properties.

RIDE uses GPU acceleration to search prepared conformer libraries. Performance depends on the query, hardware, and database access speed; see the benchmark notes.

RIDE applications include:

• Virtual screening - efficiently screen "giga-sized" libraries.
• Scaffold hopping - discover structurally novel chemicals based on a lead.
• Hit follow-up - quickly discover new chemicals with similar 3D pharmacophoric binding properties to your lead.

A simple web-based interface is provided for the ease of use by chemists, or can be used in the ICM-Pro software. In either format, RIDE allows fine-tuning of the queries to generate most desirable hit lists. This includes:

• Atom Weighting - Contributions of different portions of the molecule can be modulated with per-atom weights to reflect relative importance of certain moieties.
• Excluded Volumes meet Shape Matching - An envelope penalty can be applied to the regions that surround all or part of the query molecule to prioritize hits without bulky extensions in constrained regions.

Prepare the template to search against:

• Convert one or more chemicals to 3D.
• If the template contains multiple compounds, they must be superimposed.

Download the pre-converted 3D database for screening:

• Download prepared conformer databases here: http://molsoft.com/addons/conf/

Setup RIDE:

• Chemistry/APF Tools/ Ride search...
• Browse to the conformer database to search. From version 3.9-3, use CTRL/Command to select multiple databases for the same search.
• Select the 3D template - e.g. double click on it in the ICM Workspace.
• Enter APFcutoff, a fraction of the template self-score on a 0-1 scale. Lower values accept more hits.
• Use the envelope penalty to discourage extensions beyond the query shape. Set the repulsion weight and exclusion margin. When using an envelope penalty or receptor excluded volume, review APFcutoff because the added penalties can reduce the number of accepted hits.
• You can choose to use an excluded volume to represent a pocket. In this case you would need to read in a PDB file and make sure your template molecules are superimposed in the pocket. Then check the excluded volume box and select the pdb structure using the drop down button. If you find chemicals that go into the restricted space this is normal because possibly no chemicals were found with better score but you can increase Repulsion Weight to get more penalty for violating excluded volume.
• Refine maps: Realign the final hits using maps with a finer grid spacing.

How to set atom weights:

Set atom weights using occupancy values on a 0-1 scale. The default is 1. Select the atoms, right-click, and choose Edit/Occupancy to change their weights. In RIDE, you can control which parts of the reference molecule are preserved during screening by adjusting the occupancy values assigned to atoms.

• Higher occupancy values (e.g., 1.0) tell RIDE that a region is important and should be preserved during the APF alignment.
• Lower occupancy values (e.g., 0.1) reduce a region's contribution to the alignment score; they do not directly specify molecular flexibility.
• For graded weighting, use values from 0.1 to 1.0.

This weighting can guide scaffold hopping and pharmacophore-focused screening toward important query features.

Interpreting RIDE Results

• Score: The Score is the sum of all atomic contributions to the overall Atomic Property Field (APF) score, plus any penalties (e.g., envelope or excluded volume). Each atom is assessed by how well its properties (such as hydrogen bonding, charge, hydrophobicity, aromaticity, and size) match the target environment. A lower score indicates a better fit.
• Strain: Ligand strain in kcal/mol. Lower values indicate less strain.
• NormScore: Score normalized by the template self-score, reported on a 0-1 scale.

• Chemistry/APF Tools/ Ride search...
• Click on the Server tab

A GPU-enabled RIDE server is available as a Docker container. Follow the installation instructions included in the download:

http://molsoft.com/distrib/docker/RIDE/

After installing and starting the RIDE server, enter its URL in the URL field. Click the refresh button next to the database selector to load the available databases.

Other parameters are the same as for local search (see above).

These historical MolSoft benchmarks illustrate the dependence of RIDE performance on hardware and query size; they are not current hardware recommendations.

• Tested GPUs: Tesla P100 (12 GB RAM) and GeForce RTX 2080 (8 GB RAM).
• In those tests, the RTX 2080 was approximately 10-15 percent faster than the P100. RIDE superposition does not require double-precision arithmetic.
• A throughput of approximately 0.5 million conformers per second was reported for a query with about 22 bonds, using approximately 200 MB of GPU memory.
• Runtime and memory requirements increase with query size and the number of templates.
• Store the conformer database on an SSD to reduce the risk of disk access becoming the bottleneck.

Benchmark a representative query and database on the intended hardware before planning a large screen.