Write an account of lead discovery and optimization problem

Sources of lead compounds

Large numbers of structural examples of libraries allowed for increasingly accurate SAR models and predictions to be made Figure 6. The purified protein is then used to establish a screening assay. First, of course, one must verify that the target is viable. This is the future of drug discovery. The read outs can assess such parameters as cytoxicity, apoptosis, and effects on cell cycle. Nevertheless, it has the advantage of computational efficiency as the receptor coordinates are fixed, simply by adjusting van der Waals parameters. Although hits identified typically bind with low affinity, between , uM, we can see how they bind to their target using x-ray crystallography. Knowledge of the binding modes of multiple structures from a combinatorial experiment and co-crystallisations allowed the chemists to envisage the possibilities for expanding the range of compounds with varying physicochemical properties to maximise both binding affinity and bioavailability. Assays must have high signal-to-noise ratios. The interactions between functional groups are also taken into account through assigning the type and geometry for groups. Many of the technologies for lead discovery overlap with lead optimization as researchers attempt to incorporate the best drug characteristics early in the process. One needs high-quality libraries that also eliminate such things as reactive functional groups.

This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule. Also, knowledge-based scoring function may be used to provide binding affinity estimates. Larger scale high throughput crystallisation of putative target proteins and crystal structure analysis will increasingly push this technology upstream into lead generation, especially when combined with a robust HT affinity binding screen for novel targets.

The enzyme itself undergoes conformational shifts in order to interact maximally with any bound compound. Large numbers of structural examples of libraries allowed for increasingly accurate SAR models and predictions to be made Figure 6.

lead optimization in drug discovery

This brute force approach relies on automation to screen high numbers of molecules in search of those that elicit the desired biologic response.

Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist.

lead compound in drug discovery

Currently, a majority of effort is at the time of injury. They are based on the assumption that the more favorable an interaction is, the greater the frequency of occurrence will be.

Lead optimization slideshare

Combining high throughput co-structure analysis with a non-functional binding affinity screen can powerfully assist lead generation and optimisation for a protein-protein interaction target. This method is known as virtual screening. Flexible ligand and rigid receptor docking For systems whose behavior follows the induced fit paradigm [ 28 , 29 ], it is of vital importance to consider the flexibilities of both the ligand and receptor since in that case both the ligand and receptor change their conformations to form a minimum energy perfect-fit complex. Then the remaining components are incrementally built-up in accordance with a set of predefined rotatable torsion angles to account for ligand flexibility. Structure-based methods are in principle analogous to high-throughput screening in that both target and ligand structure information is imperative. This helps reduce false positives. Potential drug targets are not necessarily disease causing but must by definition be disease modifying. Using a thermodynamic binding screen2 coupled to x-ray structure determination of co-crystals of lead compounds with a construct of hdm2 protein, at 3DP we have been able to make quite rapid progress with this difficult target. The design of the screening library also is critical. Drug Discovery World 3 1 ,
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Molecular Docking: A powerful approach for structure