Lead Optimization

Lead Optimization

Efficient design of potent and selective molecules requires the use of a wide variety of technology and approaches. OpenEye provides solutions problems in lead optimization based on “cutting edge science”. 

Pose Prediction


Accurate, reliable poses in a protein binding site. The key advantage to using POSIT is that the returned poses are not only scored, but are annotated with a confidence or probability that the pose is correct. This allows much more informed application of resources (assay, synthesis, purchase) based on POSIT’s predictions.

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In the absence of protein structure useful predictions of molecular alignment and posing are provided by ROCS in the high accuracy subROCS mode. Exhaustive exploration of mutual alignments by subROCS provides significantly more accurate alignments than can be obtained from ROCS in the standard, high throughput mode.

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Scaffold Hopping

The discovery of new molecular classes is enabled in two ways:


Whole molecule replacements using shape and electrostatic similarity. Physically realistic electrostatic potential comparisons allow the identification of biologically active molecules with substantially different structures to existing known actives.

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Fragment replacement. The same accurate estimation of shape and electrostatic similarity used in ROCS and EON for whole molecule comparison are used in BROOD to score and rank candidate fragments to replace selected parts (the core or a side-chain) of a biologically active molecule. BROOD can also suggest fragment hypotheses for both linking small molecules and cyclization.

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Affinity Optimization


Hypotheses for potency optimization based on water energetics. Gameplan performs rapid yet physically rigorous calculation of the energetics of water at points in a protein binding site close to the ligand that are accessible by simple chemical modifications to that ligand. This provides easy to interpret suggestions for manipulations of a molecular scaffold or additions/extensions to that scaffold to improve binding affinity using an understanding of both the enthalpic and the entropic contributions to water stability.

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Pose Stability


A rapid yet reliable estimate of the free energy of molecular conformation(s). Understanding the stability of a computed pose or conformation for a molecule is central to two important problems; pose re-scoring and comparing hypotheses for the reduction of conformational flexibility. Freeform computes both enthalpic and entropic contributions to pose stability, thereby providing testable hypotheses on the effect of rigidification or cyclisation on a lead molecule’s binding affinity.

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For more detailed information on our Lead Optimization products, check out the links below:

 Documentation   >   Evaluate


Lead Optimization - Technology and Solutions

Figure 1: Freeform can be used to answer questions on the viability of rigidification or cyclisation hypotheses; is the chemistry effort required to synthesise cyclic or rigid analogues likely to result in increased potency?