Biomedical subjects

D J Danziger

Publications and source records attributed to D J Danziger.

3 recordsLinked to original sources

PubMed1989

Automated site-directed drug design: a general algorithm for knowledge acquisition about hydrogen-bonding regions at protein surfaces.

This is the first of four papers that begin to explore the possibility of automated site-directed drug design. A general outline is given of the logical steps involved in approaching the problem. The starting point is the process of knowledge acquisition about the site. An algorithm is described here for the construction of a map of hydrogen-bonding regions at protein surfaces directly from the Brookhaven Protein Data Bank coordinates. Hydrogen-bonding atoms are located, intramolecular bonds are searched for, hydrogen-bonding atoms at the surface are found and hydrogen-bonding regions are computed at the accessible surface. A grid is placed within each region discovered and the probability of hydrogen bonding at each grid point is computed. The output of the program is a map of hydrogen-bonding regions displayed within a user-defined window. This information can be used as part of a knowledge base for the automatic construction of novel ligands to fit specified binding sites.

Algorithms↗

PubMed1989

Automated site-directed drug design: the prediction and observation of ligand point positions at hydrogen-bonding regions on protein surfaces.

The HSITE program proposed in the previous paper was written to define putative ligand-point regions that could be found at protein surfaces. These regions would represent positions for hydrogen-bonding acceptor and donor atoms. In this paper the prediction of the location of these regions is compared with: (1) the position of the oxygen atoms of water molecules on the hydrated proteins myoglobin and plastocyanin; and (2) the position of hydrogen-bonded atoms in methotrexate and NADPH co-crystallized with dihydrofolate reductase, and in amidinophenyl-pyruvate co-crystallized with trypsin. The prediction of ligand-point regions is in agreement with the surveys of experimental data for water-molecule positions in protein crystals and with the positions of hydrogen-bonding atoms found in co-crystallized ligands.

Drug Design↗

PubMed1985

The search for functional correspondences in molecular structure between two dissimilar molecules.

Where structural similarities between molecular ligands are suspected in competitive binding, these similarities may be represented by a set of correspondences between analogous ligand points in the two molecules. This paper describes an algorithm which searches through all possible sets of this form, to find the one which gives the best geometric fit between matched points. Two parameters are supplied to the algorithm, giving the number of correspondences required and the tolerance permitted in the fit. A tree-search technique is used, and methods are described which prune the tree and thus limit the search. The marine neurotoxins, saxitoxin and tetrodotoxin, are used to test a computer implementation of the procedure.

Binding, Competitive↗