PubMed · 9265733
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1997. Protein engineering.. https://doi.org/10.1016/s0958-1669(97)80077-8
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Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatinase-B was desired. Previously published work with peptidyl hydroxamates and thiols indicated that while preparing gelatinase selective inhibitors was straightforward, there was not an obvious route to selective inhibitors of collagenase-1. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1 and gelatinase-B substrate hydrolysis. A method for estimating the IC50 values of compounds generated by high-throughput parallel synthesis aided in the identification of compounds with the desired properties. We have found that thiol diketopiperazines derived from nitrophenylalanine are both potent and selective inhibitors of collagenase-1. In addition, we have demonstrated that combinatorial chemistry can be utilized to identify molecules with a desired selectivity profile without access to the traditional tools of rational drug design.
Self-organizing molecular field analysis (SOMFA) is a novel technique for three-dimensional quantitative structure-activity relations (3D-QSAR). It is simple and intuitive in concept and avoids the complex statistical tools and variable selection procedures favored by other methods. Our calculations show the method to be as predictive as the best 3D-QSAR methods available. Importantly, steric and electrostatic maps can be produced to aid the molecular design process by highlighting important molecular features. The simplicity of the technique leaves scope for further development, particularly with regard to handling molecular alignment and conformation selection. Here, the method has been used to predict the corticosteroid-binding globulin binding affinity of the "benchmark" steroids, expanded from the usual 31 compounds to 43 compounds. Test predictions have also been performed on a set of sulfonamide endothelin inhibitors.
IcePick is a system for computationally selecting diverse sets of molecules. It computes the dissimilarity of the surface-accessible features of two molecules, taking into account conformational flexibility. Then, the intrinsic diversity of an entire set of molecules is calculated from a spanning tree over the pairwise dissimilarities. IcePick's dissimilarity measure is compared against traditional 2D topological approaches, and the spanning tree diversity measure is compared against commonly used variance techniques. The method has proven easy to implement and is fast enough to be used in selection of reactants for numerous production-sized combinatorial libraries.