Mini-Reviews in Medicinal Chemistry, Volume 4, No. 7, 2004
Contents
Biological
Inhibitors
Executive
Editors: Atta-ur-Rahman / M. Iqbal Choudhary
Inhibitors of Platelets Glycoprotein IIb/IIIa
(GP IIb/IIIa) Receptor: Rationale for their Use in Clinical Cardiology Pp. 703-709
Nitrogen-Containing Bisphosphonate Mechanism
of Action Pp. 711-719
Alfred
A. Reszka and Gideon A. Rodan
The Relationship Between Inhibitors of
Eukaryotic and Prokaryotic Serine Proteases Pp. 721-739
Monika
I. Konaklieva and Balbina J. Plotkin
Inducible Nitric Oxide Synthase Inhibition by
Mycophenolic Acid Pp.
741-746
Dj.
Miljkovic, M. Markovic and V. Trajkovic
Inhibitors of Types I and II Dehydroquinase Pp. 747-756
Christine
Le Sann, Mary A. Gower and Andrew D. Abell
Enzyme Inhibitors in Biorational Approaches
for Pest Control Pp. 757-767
Angel
Guerrero and Gloria Rosell
Matrix Metalloproteinases and Colon
Anastomosis Repair: A New Indication for Pharmacological Inhibition? Pp. 769-778
M.S.
Agren, L.N. Jorgensen and J.-M. Delaisse
General Reviews
Virtual Screening in Structure-Based Drug
Discovery Pp. 100%-791
X.
Barril, R.E. Hubbard and S.D. Morley
Homology-Based Modelling of Targets for
Rational Drug Design Pp.
793-804
Heather
Wieman, Kristin Tondel, Endre Anderssen and Finn Drablos
Synthesis and Biological Properties of
Fullerene-Containing Amino Acids and Peptides Pp. 805-814
Davide
Pantarotto, Nikos Tagmatarchis, Alberto Bianco and Maurizio Prato
Abstracts
[Back to top] Inhibitors of Platelets Glycoprotein IIb/IIIa
(GP IIb/IIIa) Receptor: Rationale for their Use in Clinical Cardiology
M.L.
Rossi and D. Zavalloni
The glycoprotein
IIb/IIIa (GP IIb/IIIa) receptor is the most important receptor involved in
platelet aggregation. A stable GP IIb/IIIa inhibition is required when a
massive platelet activation triggers thrombosis. Three GP IIb/IIIa inhibitors
are currently approved for clinical use: abciximab, tirofiban and integrilin.
Their different pharmacodynamic and pharmacokinetic properties reflect a
different efficacy in platelet inhibition.
[Back to top] Nitrogen-Containing Bisphosphonate Mechanism
of Action
Alfred
A. Reszka and Gideon A. Rodan
The current
paradigm for drug discovery requires the identification of a target involved in
the disease process (e.g. enzyme or receptor) and the development of an appropriate
ligand (activator, inhibitor or selective modulator). Selection of ligands for
clinical development is based on the therapeutic window between efficacy vs.
safety and ADME (absorption, distribution, metabolism and elimination)
considerations. For bisphosphonates (BPs) the process has not followed that
paradigm. BPs have very low absorption and are retained in bone, their target
tissue. A few have been used on a limited basis for over 20 years in diseases
of rapid bone destruction (e.g. post-menopausal osteoporosis, Paget’s disease,
bone metastases, etc.), without understanding their molecular mechanism of
action. The nitrogen-containing BPs (N-BPs) are the latest and most potent
addition to this family of compounds and have the widest use. They have high
potency, are specifically targeted to the osteoclast on bone and are used at
very low doses (5-10 mg clinically). Over the last four years, there was
significant progress in elucidating the mechanism of action of BPs, both
lacking and containing nitrogen. This review will focus on the mechanism of
action of the N-BPs, specifically alendronate (ALN) and risedronate (RIS), the
two agents most widely used. For these and all other N-BPs, the molecular
target is the isoprenoid biosynthetic enzyme, farnesyl diphosphate synthase, in
the cholesterol biosynthesis pathway. Although inhibition of this enzyme by
N-BPs results in the suppression of sterol biosynthesis, it is actually
disruption of a branch pathway, isoprenylation, that is responsible for N-BP
pharmacological activity. Isoprenylation involves covalent linkage of the 15 or
20 carbon isoprene moiety farnesyl diphosphate or geranylgeranyl diphosphate,
respectively, to the carboxy-terminus of regulatory proteins, including the
small GTPases Ras, Rac, Rho and Cdc42. The latter three, as well as numerous
others, are geranylgeranylated and play a rate-limiting role in the activity of
the bone-resorbing osteoclast. This targeted osteoclast inhibition accounts for
the potency of the N-BPs and for their ability to elicit the desired
therapeutic response of suppressing bone turnover. The occasional
gastrointestinal irritation caused by N-BPs appears to be mechanism-based and
is also briefly reviewed.
[Back to top] The Relationship Between Inhibitors of
Eukaryotic and Prokaryotic Serine Proteases
Monika
I. Konaklieva and Balbina J. Plotkin
The ability to
inhibit serine proteases is a major focus in the pharmaceutical industry.
Serine proteases of medical importance range in phylogenetic diversity from the
metallo-proteases, which play a role in pulmonary hypertension, and destruction
of the lung parenchyma in emphysema, to those proteases (betalactamases), which
play a role in the resistance of bacteria to beta-lactam antibiotics. In both
the mammalian and microbial systems, the development of serine protease
inhibitors has been a focal strategy spurring investigations in the area of
serine protease dependent prodrugs that incorporate a bactericidal moiety as
well as other classes of metalloprotease inhibitors.
[Back to top] Inducible Nitric Oxide Synthase Inhibition
by Mycophenolic Acid
Dj. Miljkovic, M. Markovic and V. Trajkovic
The focus of this
review is the influence of an immunosuppressive xenobiotic drug mycophenolic
acid on the induction of nitric oxide production in various cell types. The
potential therapeutic significance of the cell-specific fine-tuning of nitric
oxide release by mycophenolic acid, as well as the mechanisms behind the drug action
are discussed.
[Back to top] Inhibitors of Types I and II Dehydroquinase
Christine
Le Sann, Mary A. Gower and Andrew D. Abell
Inhibitors of
varying potency have been developed for types I and II 3-dehydroquinate dehydratase
(dehydroquinase), enzymes from the shikimate and quinate pathways that catalyse
the dehydration of dehydroquinate to dehydroshikimate. These inhibitors have
resulted from enzyme mechanistic studies and from the direct search for enzyme
inhibitors with herbicidal, fungicidal or antimicrobial potential. This review
discusses the design of the various inhibitors that have been produced so far
and some structure-activity relationships. The majority of these inhibitors are
based on dehydroquinate analogues, although some work has also been carried out
on dehydroshikimate and bissulfonamides. Some discussion is also presented on
advances in the synthesis of these types of compounds.
[Back to top] Enzyme Inhibitors in Biorational Approaches
for Pest Control
Angel
Guerrero and Gloria Rosell
Conventional
insecticides of broad spectrum have been widely used as the main tools for
controlling insect pests. However, as the consequence of their toxicity and deep
environmental impact, new biorational, and more specific approaches have been
developed. In this review we present an overview of those pest control
approaches which have resulted from studies dealing with inhibition of the
enzymes involved in the physiology, growth, molting, development and
reproduction of insect pests. These approaches involve synthetic compounds from
laboratory studies and natural chemicals present in the crop plants. Recent
developments using inhibitors expressed in transgenic plants are also outlined.
[Back to top] Matrix Metalloproteinases and Colon
Anastomosis Repair: A New Indication for Pharmacological Inhibition?
M.S.
Agren, L.N. Jorgensen and J.-M. Delaisse
Excessive matrix
metalloproteinase activities have been implicated in the pathogenesis of
intestinal anastomotic dehiscence, a serious and potentially life-threatening
complication following gastrointestinal surgery. In this review, the properties
of matrix metalloproteinases are summarized followed by presentation of
clinical therapeutic interventions with synthetic matrix metalloproteinase
inhibitors and novel experimental data on colon anastomosis repair that warrant
exploration of these drugs in surgical colorectal patients.
[Back to top] Virtual Screening in Structure-Based Drug Discovery
X. Barril, R.E. Hubbard and S.D. Morley
Recent advances in
structure determination and computational methods have encouraged the development
of structure-based virtual screening. Here we survey progress in the field and
review the most recent methods, validation experiments and real applications,
including an in-house example of hit identification for the oncology target
Hsp90. These results provide a basis for discussing the current state of
structure-based virtual screening and to outline the developments that are
expected to have a major impact in the near future.
[Back
to top] Homology-Based
Modelling of Targets for Rational Drug Design
Heather
Wieman, Kristin Tondel, Endre Anderssen and Finn Drablos
The current status
in rational drug design using homology-based models is discussed, with focus on
template selection, model building, model verification and strategies for drug
design based on model structures. A novel approach for identification of unique
binding site features from homology-based models, Protein Alpha Shape
Similarity Analysis (PASSA) is described.
[Back
to top] Synthesis and
Biological Properties of Fullerene-Containing Amino Acids and Peptides
Davide Pantarotto, Nikos Tagmatarchis, Alberto Bianco
and Maurizio Prato
Organofullerene
derivatives have shown a great potential in a wide variety of biological
activities such as DNA photocleavage, HIV-protease inhibition, neuroprotection
and apoptosis. Among the plethora of functionalized organofullerenes that have
been synthesized, fullerene-based amino acids are particularly appealing for
structural studies and biological applications. When the fullerene-framework is
incorporated into peptides, its original properties can be substantially
modified. In addition, the water-solubility of the fullerene derivatives is
enhanced, which makes such molecules amenable to biological studies.
In this review,
recent advances in the growing field of medicinal chemistry of fullerene
derivatives will be discussed. Emphasis will be given to the synthesis of the
biggest unnatural amino acid 3,4-fulleroproline (Fpr) and its derivatives. For
example, Fpr derivatives have been found to interact with different hydrolytic
enzymes and selectively discriminate between rationally designed peptides.
Fullerene-based peptides have been found to substantially activate enzymes
involved in the oxidative deamination of biogenic amines. In addition, their
membranotropic properties and effects on the structure and permeability of the
lipid bilayer of phosphatidylcholine liposomes as well as the transmembrane
transport of bivalent metal ions have been studied. Finally, applications in
medicinal chemistry of such types of amino acids and peptides will be
highlighted.