No abstract

Finding novel leads from which to design drug molecules has traditionally been a matter of screening and serendipity. We present a method for finding a wide assortment of chemical structures that are complementary to the shape of a macromoleculer receptor site whose X-ray crystallographic structure is known. Each of a set of small molecules from the Cambridge Crystallographic Database (Allen; et al. J. Chem. Doc. 1973, 13, 119) is individually docked to the receptor in a number of geometrically permissible orientations with use of the docking algorithm developed by Kuntz et al. (J. Mol. Biol. 1982, 161, 269). The orientations are evaluated for goodness-of-fit, and the best are kept for further examination using the molecular mechanics program AMBER (Weiner; Kollman J. Comput. Chem. 1981, 106, 765). The shape-search algorithm finds known ligands as well as novel molecules that fit the binding site being studied. The highest scoring orientations of known ligands resemble binding modes generated by interactive modeling or determined crystallographically. We describe the application of this procedure to the binding sites of papain and carbonic anhydrase. While the compounds recovered from the Cambridge Crystallographic Database are not, themselves, likely to be inhibitors or substrates of these enzymes, we expect that the structures from such searches will be useful in the design of active compounds.

We develop an extension of conventional distance geometry techniques that treats two or more molecules as a single "ensemble". This extension can be used to find a common pharmacophore, i.e., the spatial arrangement of essential groups, from a small set of biologically active molecules. The approach can generate, in one step, coordinates for the set of molecules in their "active" conformations such that their essential groups are superimposed. As an example, we show how the nicotinic pharmacophore can be deduced from a set of four nicotinic agonists: nicotine, cytisine, ferruginine methiodide, and muscarone. Three essential groups in each agonist are chosen: the cationic center (A), an electronegative atom (B), and an atom (C) that forms a dipole with B. There is only one pharmacophore possible for the superposition of these essential groups: a triangle with sides 4.8 A (A-B), 4.0 A (A-C), and 1.2 A (B-C). The pharmacophore triangle, which is consistent with previous models in the literature, can also be achieved by the agonist trans-3,3'-bis[(trimethylammonio)methyl]azobenzene and the antagonists strychnine, trimethaphan, and dihydro-beta-erythroidine. An examination of the common volumes of agonists suggests a specific disposition of molecular volume relative to the pharmacophore triangle. We discuss the relative strengths and drawbacks of the ensemble approach vs. other conformational search methods.

We present a method to explore the interaction of flexible ligands with receptors of known geometry on the basis of molecular shape. This method is an extension of that described by Kuntz et al. (J. Mol. Biol. 1982, 161, 269). The shape of a binding site on a macromolecular receptor is represented as a set of overlapping spheres. Each ligand is divided into a small set of large rigid fragments that are docked separately into the binding site and then rejoined later in the calculation. The division of ligands into separate fragments allows a degree of flexibility at the position that joins them. The rejoined fragments are then energy minimized in the receptor site. We illustrate the method with two test cases: dihydrofolate reductase/methotrexate and prealbumin/thyroxine. For each test case, the method finds binding geometries for the ligand near that observed crystallographically as well as others that provide good steric fit with the receptor.

A simple and efficient method to induce porosity both in the core and on the surface of electrospun submicrometer polymer fibers has been demonstrated by combining nonsolvent-induced phase separation with electrospinning. In this modified electrospinning process, fibers are collected in a bath filled with a nonsolvent for the polymer being electrospun. The presence of residual solvent in the nanofibers causes phase separation once the fibers reach the nonsolvent bath. Poly(acrylonitrile) (PAN) in dimethylformamide (DMF) is chosen as the model polymer/solvent system. The versatility of the approach is demonstrated by extending the technique to poly(styrene)/DMF, poly(styrene)/toluene, and poly(methyl methacrylate)/DMF systems. With a suitable solvent (ethanol) and optimized tip-to-collector distance, the specific surface area of the porous PAN fibers increased to an order of magnitude compared to that of the smooth fibers obtained by the conventional electrospinning. Further, this electrospinning technique is extended to coreÀshell electrospinning, enabling the fabrication directly in one step of PAN-based hollow fibers having porosity both in the surface and the bulk.