Biomedical subjects

M C Nicklaus

Publications and source records attributed to M C Nicklaus.

23 records · Page 2Linked to original sources

PubMedDate not supplied

National Cancer Institute Drug Information System 3D database.

A searcheable database of three-dimensional structures has been developed from the chemistry database of the NCI Drug Information System (DIS), a file of about 450,000 primarily organic compounds which have been tested by NCI for anticancer activity. The DIS database is very similar in size and content to the proprietary databases used in the pharmaceutical industry; its development began in the 1950s; and this history led to a number of problems in the generation of 3D structures.

Antineoplastic Agents↗

PubMedDate not supplied

Molecular modeling in the discovery of drug leads.

The National Cancer Institute of the U.S.A. maintains a repository of about 500,000 chemicals which it has tested at some time for anticancer activity. As new chemotherapeutic targets present themselves, methods have been developed by which this large database can be re-examined without resorting to expensive high-volume biological screening. Electronic screening, the method described in this paper, begins with the identification of a target enzyme. The pharmacophore used by the enzyme in binding to substrates is identified, and then all compounds in the database that contain the pharmacophore are found. These compounds are then further filtered, for example, by physical properties such as solubility, and the relatively small number of compounds that survive are submitted for biological testing. This use of a primary electronic screen in the search for ligands of protein kinase C is described. The screen is very fast, and the method is quite generally applicable to different enzymes.

Antineoplastic Agents↗

PubMedDate not supplied

Computational chemistry on commodity-type computers.

A number of inexpensive computers were benchmarked with the ab initio program Gaussian 94, using both small standard test jobs and larger density functional (DFT) calculations. Several varieties of Pentium (x86) and Alpha CPU based systems were tested. Most of them were running under the open source code operating system Linux. They were compared with several workstations and supercomputers. The most powerful of today's commodity-type processors surpassed current supercomputers in speed. The choice of compilers and compilation options was often found to have a larger influence on job CPU times than details of the hardware. Especially on the x86 type machines, the jobs always ran faster the less memory (RAM) they were given. The fastest machine on a per-CPU basis was an Alpha/Linux system. For the DFT calculation, it was close to twice as fast as a Cray J90 supercomputer.

Chemistry↗

PubMedDate not supplied

Conformationally restricted nucleosides. The reaction of adenosine deaminase with substrates built on a bicyclo[3.1.0]hexane template.

Adenosine deaminase (ADA) can discriminate between two distinct (North and South), conformationally rigid substrate conformers. (N)-methanocarba-2'dA (4) is deaminated 100 times faster than the antipodal (S)-methanocarba-2'dA (5), whereas a non-rigid analogue, aristeromycin (6), is deaminated at an intermediate rate. These results are in agreement with crystallographic data from ADA-ribonucleoside complexes showing the furanose ring of the bound purine in a C3'-endo (North) conformation. The data presented here suggests that 4 and 5 are useful probes to ascertain conformational preferences by purine metabolizing enzymes.

Adenosine Deaminase↗

PubMedDate not supplied

Inhibition of (cytosine C5)-methyltransferase by oligonucleotides containing flexible (cyclopentane) and conformationally constrained (bicyclo[3.1.0]hexane) abasic sites.

Pseudorotationally locked sugar analogues based on bicyclo[3.1.0]-hexane templates were placed in DNA duplexes as abasic target sites in the M. HhaI recognition sequence. The binding affinity of the enzyme increases when the abasic site is constrained to the South conformation and decreases when it is constrained to the North conformation. A structural understanding of these differences is provided.

Bridged Bicyclo Compounds↗