CROs for Drug Discovery

CROs for Drug Discovery: Partners for Research

CROs (Contract Research Organizations) are companies specialized in independently conducting in-house R&D. They often have capabilities in synthesis, design, and testing, allowing them to serve as supportive or leading partners for pharmaceutical companies and other organizations that lack these capabilities. CROs assist in one or more projects, providing expertise to accelerate research processes and drug development.

A good CRO (Contract Research Organization) stands out by being multidisciplinary, offering its services as a comprehensive package where clients receive fully detailed information to advance their projects. However, it's also possible for clients to opt for specific services, such as the synthesis of a compound series, conducting virtual screenings, or structural elucidation of a target protein.

In all cases, a CRO should be versatile and well-equipped to provide the best results, ensuring flexibility to cater to diverse client needs.

Elucidating SARs

CROs involved in small molecule drug design are frequently tasked with addressing the question of how to successfully optimize a compound series. This is typically approached by synthesizing analogs of a bioactive compound, iteratively exploring which modifications influence biological activity. Establishing structure-activity relationships (SAR) enables researchers to identify and select favorable modifications that enhance the compound's potency.

The elucidation of SARs can be carried out by the medicinal chemistry or computational chemistry team, or through collaboration between both, depending on the initial resources that come with the project. In the context of rational design, analogs are evaluated for synthesis, focusing on those that introduce additional interactions between the ligand and the target structure. These compounds are then synthesized and tested. Through an iterative process, insights are gained into which functionalities increase or decrease potency. If needed, the binding mode hypothesis is adjusted based on new findings to establish a clearer correlation between structure and activity.

Tools for Establishing SARs

Establishing SARs requires several interconnected elements. This includes predicting the binding mode of a ligand (or series) when no crystal structure is available, and generating ideas on how to improve a compound. In between, there must be a control mechanism to validate the plausibility of the results, preventing the pursuit of incorrect leads. This ensures resources are not wasted on synthesizing compounds that lack potential for success.

For example, it is not productive to synthesize multiple analogs that introduce decorations at positions leading to clashes with the target surface. However, synthesizing a single compound can provide insight that no groups are tolerated at that position, thereby supporting the initial binding mode hypothesis. In another step, attention can shift to positions where more space is available, exploring groups that, according to predictions, could enhance potency through additional interactions, starting with the most promising functionalities.

In this area, medicinal chemists can collaborate effectively with computational chemists, engaging in a dialogue to efficiently plan the next steps.

Helpful Tools to Establish SARs

In an effort to support scientists working in lead optimization and small molecule drug discovery, we at BioSolveIT have developed software tailored to everyday needs, effectively guiding users in making the right decisions.

Spotting areas to improve: The overall binding affinity of a molecule is composed of various factors, primarily driven by the individual contributions of each heavy atom to the total binding affinity. Identifying problem areas within the molecule can help pinpoint which regions are currently suboptimal and where improvements are needed. Examples include hydrophilic atoms that are unsatisfied in a lipophilic binding pocket or ring carbons that could form better interactions if replaced with nitrogen.
For this purpose, we developed SeeSAR, which uses HYDE scoring to enable such assessments. Users can immediately identify which regions need improvement and receive detailed information on individual contributions.
Evaluating docking predictions: Predicting a binding mode is often the cornerstone for subsequent rational design, as the 3D information defines the structures to be pursued. Therefore, it is essential to find poses that are credible. SeeSAR supports hypothesis formulation through predictions of potential binding sites and the placement of (potential) ligands into the defined cavity. Poses can then be easily checked for plausibility with various parameters such as molecular torsions, fulfillment of specific interaction patterns, as well as intra- and intermolecular clashes.
Ideating on the next compounds to synthesize: Planning saves a lot of money. By thinking ahead about which compounds to create, unnecessary effort and material usage can be saved. Therefore, once a concept for how a ligand could bind is developed, it makes sense to explore which modifications could improve the potency of the compound and which positions are not the most promising sites for additional groups.
This can be done by manually testing derivatives or by asking the program for ideas that might lie outside the possibilities one might have considered.

SeeSAR's Molecule Editor Mode allows users to make modifications independently and see their effects on the calculated affinity value. Additionally, SeeSAR's Inspirator Mode provides a suite of tools for exploring potential new modifications. This includes compound extension, replacement of groups and scaffolds, and analoging for small modifications based on common medicicnal chemistry transformations.

BioSolveIT software for SAR elucidation:

SeeSAR: A drug design dashboard developed for both computational and medicinal chemists.
The easy-to-use interface enables team members to address specific drug design questions, such as binding modes and suggestions for improving compounds. The visual GUI helps make decisions based on scientific evidence and allows individuals to complement their own expertise in molecular design with new, creative methods to more effectively develop better compounds.

Command-line tools for SAR elucidation:

FlexX: Docking algorithm.
HYDE: De-solvation-aware scoring algorithm. Displays individual contributions of heavy atoms to the overall binding affinity of the ligand.

Communicating Your Results

For CROs for drug discovery, it is of utmost importance to communicate your results efficiently within the organization and to the customer, while presenting scientifically sound arguments to validate the plausibility of the approach.

Exporting results in various formats allows for clear communication and analysis. Support for stunning 3D models in the .glb format takes PowerPoint presentations to the next level, enabling dynamic, visual communication of binding modes and the compound optimization process. Sharing projects with annotations fosters cross-team collaboration, where each member can follow the thought process of others. CROs in drug discovery gain an additional team member with SeeSAR, engaging in an interactive dialogue with the teams, contributing to unprecedented successes.

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