Drug Design Reviews - Online, Volume 2, No. 2, 2005
Contents
Molecular Mechanisms of Resistance to
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase
Pp.101-113
Arrest of Amyloid Fibril Formation Associated
to Type II Diabetes:Structural and Functional Links to the Mechanism of
Alzheimer’s b-Amyloid
Fibrillization Pp.115-119
The Glutathione System as an Attractive
Therapeutic Target Pp.121-127
Lung Remodeling in Asthma: A New Target of
Anti-Asthma Therapy Pp.129-136
Discovery of Small Molecule Inhibitors for
Prevention of Complement-Mediated Immune Hemolysis Pp.137-143
A Binding Affinity Based Computational
Pathway for Active-Site Directed Lead Molecule Design: Some Promises and
Perspectives Pp.145-165
New Physiological Targets Within the Kidney
for Antihypertensive Therapy Pp.167-178
Abstracts
[Back to top] Molecular Mechanisms of Resistance to
Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse
Transcriptase
Current treatments for human immunodeficiency virus (HIV) infection target viral enzymes such as the protease and the reverse transcriptase (RT), as well as the envelope glycoprotein gp41. RT inhibitors include nucleoside and nonnucleoside inhibitors that bind to distinct sites within the polymerase. Zidovudine, stavudine, zalcitabine, didanosine, lamivudine, abacavir, tenofovir and emtricitabine are converted to active triphosphate analogues and incorporated into the nascent viral DNA in reactions catalyzed by HIV RT. Since nucleoside analogues lack the 3’-OH group required for the phosphodiester bond formation, they act as chain terminators of DNA synthesis. Development of drug resistance is a major hurdle towards their long-term efficacy. Mutations in the pol gene selected during treatment with nucleoside analogues confer resistance through different mechanisms: (i) altering discrimination between nucleoside RT inhibitors and natural substrates (dNTPs), or (ii) increasing the RT’s phosphorolytic activity, which in the presence of ATP and other pyrophosphate donors allows the removal of chain-terminating nucleotides from the 3’ end of the primer. These mechanisms are also relevant for multidrug resistance, as shown for the Q151M complex, or RTs having thymidine analogue resistance mutations and/or insertions at codons 69-70 of the fingers subdomain.
[Back to top] Arrest of Amyloid Fibril Formation Associated
to Type II Diabetes:Structural and Functional Links to the Mechanism of
Alzheimer’s b-Amyloid
Fibrillization
Pancreatic amyloid deposits composed of the islet amyloid polypeptide (IAPP) are found in nearly all type II diabetes patients. These fibrillar deposits are cytotoxic and their production is clearly associated with the progression of pancreatic b-cells death. Such progressive formation of cytotoxic amyloid fibrils by IAPP in Type II diabetes is parallel in many ways to the process of cerebral amyloid fibril formation by the b-amyloid polypeptide in the case of Alzheimer’s disease. Another line of parallelism between Alzheimer’s disease and Type II diabetes is the occurrence of a mutation within the IAPP gene that is correlated with an early onset of Type II diabetes in the Asian population. This finding resembles the occurrence familial mutations within the b-amyloid polypeptide that are correlated with early onset of Alzheimer's disease. Biochemical and biophysical analysis demonstrated an increased amyloidogenic potential as well as cytotoxicity for the altered IAPP protein. Arrest of amyloid formation by IAPP therefore seems to be significant to halt the deterioration in b-cell function of Type II diabetes patients and maybe used as a treatment to delay onset for parts of the population with predisposition for this disease. Extensive studies by several academic and industrial groups already resulted in lead molecules that can inhibit amyloid fibril formation by IAPP. Some of these lead molecules are based of the same methodologies that were successfully used for the development of potential drugs that inhibit formation of amyloid fibrils by the b-amyloid polypeptide.
[Back to top] The Glutathione System as an Attractive
Therapeutic Target
Thiol-containing compounds are central actors in many biochemical and pharmacological reactions. The response of cells to any stress (including cell division and apoptosis) involves changes in thiol content as they are consumed to protect cells via different actions (direct modification/regulation of biomolecules, antioxidativity, detoxification, signal transmission). The story of glutathione, the basic intracellular thiol-containing compound, ranges throughout different scientific fields. The importance of this biomolecule is highly impressive. Reduced glutathione (GSH) is a principal actor in many physiological and pharmacological reactions. There are about 60 000 entries under “glutathione” found in the Medline database. The aim of this short review is to characterize glutathione and show that due to an intriguing and multifaceted biofunctionality in the human body this tripeptide itself, as well as its analogues, belongs to the group of molecules looking for broad clinical use (besides being excellent antioxidants). This information might draw more attention to the discovery and investigation of glutathione system supporting/relating substances with a substantial clinical impact.
[Back to top] Lung Remodeling in Asthma: A New Target of
Anti-Asthma Therapy
It has been established that airway inflammatory processes are pivotal as the pathological features of bronchial asthma. Standard therapy with inhaled corticosteroids markedly suppresses such inflammatory changes, resulting in clinical beneficial effects. However, it is now clear that several histological changes including goblet cell hyperplasia, sub-epithelial collagen deposits, increased capillary networks and smooth muscle hypertrophy occur as a chronic consequence of this airway disorder even by the recommended strategies with steroid treatment. These pathologic changes, so-called remodeling, play an important role in the increased airway obstruction and hyperresponsiveness, and eventually in the development of irreversible respiratory failure. Recent studies have elucidated that myofibroblasts and smooth muscle cells play a vital role in these processes. Therefore, agents regulating proliferation and differentiation of these cells may become new therapeutic strategies for the near future.
[Back to top] Discovery of Small Molecule Inhibitors for Prevention of
Complement-Mediated Immune Hemolysis
The complement system plays an essential role in host defense against infectious agents, but can cause substantial damage to self-tissues when activated inappropriately, contributing to the pathology of a large number of diseases including autoimmune diseases, adult respiratory distress syndrome and stroke. In the transfusion medicine setting, complement sensitization of red blood cells (RBCs) can result in life-threatening hemolytic transfusion reactions as well as hemolytic anemias. There is thus a critical need for a therapeutically applicable inhibitor to reduce complementmediated RBC destruction. To date several potent complement inhibitors that act at various steps in the complement activation cascade have been described, some of which have been tested in preclinical animal models as well as in human clinical trials. However, none of these has yet been adopted as a therapeutic agent for prevention of immune hemolysis. The potential of developing selective and potent complement inhibitors for the effective and safe prophylactic use and treatment of hemolytic transfusion reactions and complement-mediated hemolytic diseases will be discussed here.
[Back to top] A Binding Affinity Based Computational Pathway for Active-Site
Directed Lead Molecule Design: Some Promises and Perspectives
Drug discovery in the 21st century is expected to be different in at least two distinct ways: development of individualized medicine utilizing genomic information and emergence of an integrated in silico protocol for facilitating target identification, structure prediction and lead discovery. The expectations from computational methods for developing suggestions on potential leads reliably and expeditiously, are continuously on the increase. Several conceptual and methodological concerns remain before an automation of lead design in silico could be contemplated. The novelty of the candidates generated, their geometries, the partial atomic charges and other force field parameters for enabling energy evaluations is one concern. A proper account of the flexibility of the candidate molecule and the target, a consideration of solvent and salt effects in binding and a reliable methodology for developing quantitative estimates of binding affinities is another. Finally the drug-likeness of the candidates generated is yet another concern. Each of these issues warrants a careful consideration. In this review, we sketch a system independent, binding free energy based, comprehensive computational pathway from chemical templates to lead-like molecules, given the three dimensional structure of the target protein and a definition of its active site, focusing on some emerging in silico trends and techniques. We survey current methods for generation of candidate molecules and some popular protocols for docking candidates in the protein active site. We discuss the theory of protein-ligand binding in the rigorous framework of statistical mechanics and assess the current strategies for affinity based filtering of candidates. We address concerns related to flexibility of the target and the candidate, solvent and salt effects in lead design. We present a realization of the pathway proposed in a high performance computing environment for cyclooxygenase-2 target wherein the computational protocols could sort drugs from nondrugs, assuring the viability of the overall strategy. We highlight a few case studies indicating the current level of agreement between theory and experiment in eliciting binding affinities. Finally, we present a critical assessment of the computational steps involved in binding affinity based active site directed lead molecule design and further improvements envisioned for potential automation.
[Back to top] New Physiological Targets Within the Kidney for Antihypertensive
Therapy
Traditional targets for antihypertensive therapy include vascular smooth muscle and endothelium, the renin/angiotensin and sympathetic nervous systems, and the renal tubules. The progressive improvement in efficacy and tolerability of antihypertensive pharmacotherapy has depended largely on development of agents that target multiple control mechanisms. For example, angiotensin converting enzyme inhibitors (and angiotensin receptor antagonists) act at all of these physiological targets. Recent basic research has identified new potential targets for antihypertensive therapy, particularly within the kidney, which should be considered both in terms of their responses to available antihypertensive agents, and in the development of newer, more effective agents. For example, there is now new information about how alterations in structure and function of the renal circulation can contribute to the development of hypertension, by causing dysregulation of glomerular filtration and renal medullary perfusion, and so the ability of the kidney to regulate salt and water balance. There is also increased understanding of how reactive oxygen species can contribute to cardiovascular disease, particularly that associated with diabetes. This new information raises the exciting possibility of future development of agents that actually target the underlying causes of hypertension, with the potential to provide prophylaxis or cure, rather than just maintenance therapy.