Mini-Reviews in Medicinal Chemistry, Volume 4, No. 10, 2004
Contents
Cheminformatics:
A New Approach for Lead Discovery
Executive
Editor: Juan A. Hueso-Rodriguez
Decision Support Systems in Drug Discovery Pp.1019-1028
Computational Techniques for Diversity
Analysis and Compound Classification Pp.1029-1039
D.B.
Kitchen, F.L. Stahura and J. Bajorath
Physicochemical Descriptors in Property-Based
Drug Design Pp.1041-1052
Oleg
A. Raevsky
Integration of Virtual Screening into the
Drug Discovery Process Pp.1053-1065
D.N.
Chin, C.E. Chuaqui and J. Singh
Methods for Library Design and Optimisation Pp.1067-1076
D.V.S.
Green and S.D. Pickett
General Reviews
Microtubulin Binding Sites as Target for
Developing Anticancer Agents Pp.1077-1104
Mohd.
N. Islam and Magdy N. Iskander
Synthetic Approaches to the 2003 New Drugs Pp.1105-1125
Kevin
K.-C. Liu, Jin Li and Subas Sakya
Abstracts
[Back to top] Decision Support Systems in Drug Discovery
Jian
Shen, Valery Polyakov, Ramesh Rachapudi and Tony You
Decision support
systems have been widely used in drug discovery owing to the complexity of data
and information involved. In this article, we review both commercially
available packages and publicized in-house made systems. All selected systems
should be able to handle chemical structures and to organize information for
decision makers, more specifically for medicinal chemists. Although we do not
rank these system, pros and cons of these systems will be discussed.
[Back to top] Computational Techniques for Diversity
Analysis and Compound Classification
D.B.
Kitchen, F.L. Stahura and J. Bajorath
Molecular
similarity and diversity analysis has played a significant role in computer-aided
drug discovery for more than a decade. Compound classification methods have
also become increasingly important for the design and organization of compound
databases and in silico screening. Here we review these related
methodologies and discuss selected applications.
[Back to top] Physicochemical Descriptors in Property-Based
Drug Design
Oleg
A. Raevsky
The contribution
of physicochemical descriptors to lipophilicity, water solubility, and
intestinal absorption and oral bioavailability in humans is considered.
Partitioning in
the octanol/water system is presented as a competition between two opposing
effects: volume and hydrogen bond acceptor ability. Water solubilities of
liquid compounds are roughly equal to their reciprocal logP values. However,
there is also a detectable contribution of H-bond donor ability to water
solubility. The main problem in predicting the solubilities of solid chemicals
and drugs is the estimation of their crystal lattice energies. QSAR approaches
that add terms such as melting point, and the product of H-bond donor and
acceptor parameters are not sufficient to make these predictions practical.
Human intestinal
absorption for passively transported drugs is almost completely correlated with
hydration processes that are determined by H-bond acceptor and donor abilities.
It is emphasized
that structural features of drug molecules have significant influences on their
properties. Classic QSAR approaches are not enough to create stable, predictive
models for diverse drugs. A combination of Similarity and QSAR approaches is
one possibility to take all physicochemical properties in addition to
structural features into account.
[Back to top] Integration of Virtual Screening into the
Drug Discovery Process
D.N.
Chin, C.E. Chuaqui and J. Singh
Advances in
high-throughput virtual screening using docking, predictive ADME methods and
their integration with informatics and high-performance computing are reviewed.
Docking approaches have led to the identification of novel active compounds.
Predictive ADME methods have improved on selective test sets with broader
training sets, though extensive validation is lacking.
[Back to top] Methods for Library Design and Optimisation
D.V.S.
Green and S.D. Pickett
The introduction
of combinatorial chemistry groups into pharmaceutical companies provoked a
desire for efficient and effective methods for library design and optimisation.
This, in turn, has resulted in a large number of scientific publications,
detailing a variety of approaches to the problem. This review attempts to
describe the major works in the literature, to set them in context both
chronologically and scientifically, and to identify the outstanding challenges
that must be addressed, if this area of research is to maintain the rapid
progress seen hitherto.
[Back to top] Microtubulin Binding Sites as Target for
Developing Anticancer Agents
Mohd.
N. Islam and Magdy N. Iskander
Microtubules (MTs)
play important and diverse roles in eukaryotic cells. Their function and
biophysical properties have made a−and b−tubulin, the main components of MTs,
the subject of intense study. Interfering with normal MT dynamics, for example,
by the addition of tubulin ligands, can cause the cell great distress and
affect MT stability and functions, including mitosis, cell motion and
intracellular organelle transport. It has been shown in the literature that tubulin
is an important target molecule for developing anticancer drugs. Tubulin
binding molecules have generated considerable interest after the successful
introduction of the taxanes into clinical oncology and the widespread use of
the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell
mitosis by binding to the protein tubulin in the mitotic spindle and preventing
polymerization into the MTs. This mode of action is also shared with other
natural agents eg colchicine and podophyllotoxin. However various tubulin
isotypes have shown resistance to taxanes and other MT agents. Therefore, there
is a strong need to design and develop new natural analogs as antimitotic
agents to interact with tubulin at sites different from those of vinca alkaloids
and taxanes. This minireview provides SAR on several classes of antimitotic
agents reported in the literature. The structures and data given are essential
to the scientists who are involved in drug design and development in the field
of anticancer drugs.
[Back to top] Synthetic Approaches to the 2003 New Drugs
Kevin
K.-C. Liu, Jin Li and Subas Sakya
New drugs are introduced
to the market every year and each individual drug represents a privileged
structure for its biological target. In addition, these new chemical entities
(NCEs) not only provide insights into molecular recognition, but also serve
as drug-like leads for designing new future drugs. To these ends, this review
covers the syntheses of 23 NCEs marketed in 2003.