Multidimensional lead optimization

This section will provide an overview on ADME models from our group to illustrate our approach for building predictive models on structurally diverse training sets. Datasets for intestinal human absorption and human serum albumin binding are discussed, while models for other relevant ADME properties have also been obtained. Those models, however, do not stand alone but are used in combination with those models tailored for affinity and selectivity in the frame of multidimensional lead optimization. 

Fig. 14.10 Example for multidimensional optimization on relevant properties during the lead optimization phase from leads to a development candidate. After some iteration, compound properties are either improved or show no further optimization potential.

The paradigm shift from critical activities from later drug development to earlier discovery phases some years ago has effectively led to a change in lead optimization and added a new dimension of complexity, while it is envisioned that from a multidimensional, data-driven process more suitable candidates in accord with the therapeutic target product profiles may emerge for the treatment of currently unmet medical needs. 

Select appropriate metrics for multidimensional optimization use ligand efficiency and lipophilic efficiency metrics in hit-to-lead optimization and change to more complex metrics emphasizing dosage to support lead optimization. 

Within the quantum formulation of OCT, the basic variational procedure leads to a set of equations for the optimal laser held, which include two Schrodinger equations to describe the dynamics starting from the initial and the target state wavepackets. The optimal laser held is given by the imaginary part of the correlation function for these two wavepackets. This system of equations of optimal control must generally be solved iteratively, making it an extremely computationally expensive approach for multidimensional systems. 

For more general problems, it has been observed that the direct product representation, which for the Fourier method implies a representation by an equally spaced Cartesian grid, is not optimal. A careful analysis of the Fourier method leads to the observation that this direct product grid is not isotropic in momentum space, so that different directions have different sampling intervals. A faithful representation of a multidimensional... 

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