Recent Advances in the Solid Phase Synthesis of Drug-Like Heterocyclic
Small Molecules. Pp. 191-210.
C. J. Andres, Derek J. Denhart, Milind S. Deshpande and Kevin W.
Gillman
[Abstract]
Structure-Based Drug Design: Combinatorial Chemistry and Molecular Modeling.
Pp. 211-221.
D. Lynn Kirkpatrick, Shawndra Watson and Saraj Ulhaq
[Abstract]
Small Molecule Recognition: Solid Angles Surface Representation and
Molecular Shape Complementarity. Pp. 223-237.
R. Norel, H. J. Wolfson and R. Nussinov
[Abstract]
Inventory Management and Reagent Supply for Automated Chemistry. Pp.
239-247.
Ed Kuzniar
[Abstract]
[Back to top] Recent Advances
in the Solid Phase Synthesis of Drug-Like Heterocyclic Small Molecules.
C. J. Andres, Derek J. Denhart, Milind S. Deshpande and Kevin W. Gillman.
Because of their synthetic challenge, broad range of physical / chemical
properties, and diverse biological activities, heterocycles continue to
be of interest to both the academic and industrial chemist. This review
covers recent advances in the solid phase synthesis of drug-like heterocyclic
small molecules. Syntheses which form the heterocycle on the solid phase
are emphasized; syntheses in which a preformed heterocycle is functionalized
on the solid support have been omitted. The majority of references are
from publication year 1999. This review should be of interest to anyone
involved in, or contemplating the solid phase synthesis of small molecule
drug-like heterocycles, especially for combinatorial chemistry applications.
[Back to top] Structure-Based
Drug Design: Combinatorial Chemistry and Molecular Modeling. D. Lynn Kirkpatrick,
Shawndra Watson and Saraj Ulhaq.
Drug discovery efforts are shifting to include the rapid synthetic
procedures of combinatorial chemistry and the elegance of rational library
design. The wealth of computational methods which explore both the receptor
structure and the ultimate pharmacophore complementarity, provide novel
avenues for chemists to discover new lead compounds or design virtual libraries
for screening prior to the synthetic stage. This mini-review provides an
overview of a few current methodologies of library generation, highlighting
docking procedures which have utility in both the discovery and optimization
stages of drug development. Three specific examples of different approaches
to the use of docking are provided. These describe the development of inhibitors
to the human A3 adenosine receptor and HIV-1 protease, and the evaluation
of the activity of novel inhibitors of the redox regulator protein, human
thioredoxin.
[Back to top] Small Molecule
Recognition: Solid Angles Surface Representation and Molecular Shape Complementarity.
.
Here we examine the recognition of small molecules by their protein
and DNA receptors. We focus on two questions: First, how well does the
solid angle molecular surface representation perform in fitting together
the surfaces of small ligands, such as drugs and cofactors to their corresponding
receptors; And second, in particular, to what extent does the shape complementarity
play a role in the matching (recognition) process of such small molecules.
Both questions have been investigated in protein-protein binding: "Critical
Points" based on solid angle calculations have been shown to perform well
in the matching of large protein molecules. They are robust, may be few
in numbers, and capture satisfactorily the molecular shape. Shape complementarity
has been shown to be a critical factor in protein-protein recognition,
but has not been examined in drug-receptor recognition. To probe these
questions, here we dock 185 receptor-small ligand molecule pairs. We find
that such a representation performs adequately for the smaller ligands
too, and that shape complementarity is also observed. These issues are
important, given the large databases of drugs that routinely have to be
scanned to find candidate, lead compounds.
We have been able to carry out such large scale docking experiments owing to our efficient, computer-vision based docking algorithms. Its fast CPU matching times, on the order of minutes on a PC, allows such large scale docking experiments.
[Back to top] Inventory
Management and Reagent Supply for Automated Chemistry. Ed Kuzniar.
Developments in automated chemistry have kept pace with developments
in HTS such that hundreds of thousands of new compounds can be rapidly
synthesized in the belief that the greater the number and diversity of
compounds that can be screened, the more successful HTS will be. The increasing
use of automation for Multiple Parallel Synthesis (MPS) and the move to
automated combinatorial library production is placing an overwhelming burden
on the management of reagents. Although automation has improved the efficiency
of the processes involved in compound synthesis, the bottleneck has shifted
to ordering, collating and preparing reagents for automated chemistry resulting
in loss of time, materials and momentum.
Major efficiencies have already been made in the area of compound management for high throughput screening. Most of these efficiencies have been achieved with sophisticated library management systems using advanced engineering and data handling for the storage, tracking and retrieval of millions of compounds. The Automation Partnership has already provided many of the top pharmaceutical companies with modular automated storage, preparation and retrieval systems to manage compound libraries for high throughput screening. This article describes how these systems may be implemented to solve the specific problems of inventory management and reagent supply for automated chemistry.