PubMed · 1624959
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R W Counts. 1992. When is an answer the answer?. https://doi.org/10.1007/bf00129429
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Screening synthetic combinatorial libraries, such as mixtures of oligo(N-substituted)glycines, facilitates rapid drug lead discovery and optimization by vastly increasing the number of candidate molecules made and tested. Discovery efficiency and productivity can be further improved by using experimental design to maximize molecular diversity for a given library size or to bias the library with key features for a specific receptor. We describe new methods to quantify molecular diversity using descriptors that characterize lipophilicity, shape and branching, chemical functionality, and specific binding features. Experimental design methods select sets of side chains that are diverse in these properties, and "flower plots" allow the diversity to be graphically compared. We also quantify the overall diversity accessible to different families of combinatorial chemistry.
A new approach to drug discovery is based on the generation of high diversity libraries of DNA, RNA, peptides or small molecules. Search of such libraries for useful molecules is an optimization problem on high-dimensional molecular fitness landscapes. We utilize a spin-glass-like model, the NK model, to analyze search strategies based on pooling, mutation, recombination and selective hill-climbing. Our results suggest that pooling followed by recombination and/or hill-climbing finds better candidate molecules than pooling alone on most molecular landscapes. Our results point to new experiments to assess the structure of molecular fitness landscapes and improve current models.
A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease. One such improvement resulted in a compound selected for preclinical studies as an antiviral agent against AIDS.