bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drug Transport and Membrane Transport Proteins
Authors: Swaan Peter W. 
Published: September 2010

AbstractIn order to exert their intended therapeutic goal, drugs need to cross epithelial barriers to reach their site of action. Transport proteins have critical physiological roles in nutrient absorption and transport of endogenous compounds. These systems can serve as useful pharmacological targets and may be utilized as a mechanism to increase drug absorption. However, there is little understanding of these proteins at the molecular level due to their resistance to crystallization. Numerous efforts have been made to characterize the P‐glycoprotein efflux pump, the peptide transporter (PepT1), and the apical sodium dependent transporter (ASBT), which are important not only for their native transporter function but also as drug targets to increase absorption and bioactivity.In vitroand computational approaches have been applied to gain some insight into these transporters and their substrate specificities. This represents an opportunity for optimizing molecules as substrates for solute transporters and providing a further screening system for drug discovery. This chapter will demonstrates that future growth in knowledge of transporter function will be lead by integratedin vitroandin silicoapproaches.
Allosteric Proteins and Drug Discovery
Authors: Bell J. Ellis , Bell Jessica K. 
Published: September 2010

AbstractThe existence of allosteric phenomena in the control of proteins allows for exquisite control of many of the cell's normal processes. Allosteric interactions involve the binding of an “allosteric” ligand to a site other than the functional (active) site of the protein, with a concomitant alteration in activity. Two major theoretical models have been presented to explain allosteric interactions, that of Monod, Wyman, and Changeux and that of Koshland, Nemethy, Filmer, Dalziel, and Engel. Although there are essential differences between the two models, both require that allosteric ligands interact with one or more forms of the protein to trigger a modulating effect. In only a few cases, much structural detail is known about more than one conformational state of any given allosteric protein, or how the binding of small‐molecule effectors to an allosteric site triggers protein modulation. Our current understanding of how conformational signals may be transmitted between proteins is assessed, particularly in the light of recent discussion of intrinsically disordered regions of proteins. Methods for identifying potential ligands that may elicit allosteric effects is also discussed. In this chapter, the essential features of allosteric enzymes and allosteric models are examined in a context that leads to consideration of how drugs may be designed such that they either mimic or block normal allosteric effects. Several existing “allosteric” drugs, and a number of potential targets for the rationale design of future allosteric drugs, are discussed.
Large‐Scale Synthesis
Authors: Gupton Frank 
Published: September 2010

Abstract
The capability to fulfill drug substance requirements to support the various elements of pharmaceutical development is an essential component of the overall drug development process. The preparation of bulk materials for toxicology, formulation development, and clinical supplies can represent a significant challenge, depending on such factors as the molecular complexity of the drug candidate, the quantities of materials required, and the state of development of the synthetic process. As a drug candidate proceeds through the various stages of drug development and into commercial launch, the challenge of process development is to ensure the uninterrupted supply of drug substance without compromising the ability to ultimately supply a commercially viable chemical process. This chapter provides a general overview of the issues and requirements associated with the development and scale‐up of chemical processes for bulk active drug substances. An account of the nevirapine process development efforts at Boehringer Ingelheim is also provided as an example of the evolution of a chemical process from the initial efforts in medicinal chemistry to commercial‐scale operations.
Physicochemical Characterization and Oral Dosage Form Selection Based on the Biopharmaceutics Classification System
Authors: Amidon Gregory E. , He Xiaorong , Hageman Michael J. 
Published: September 2010

Abstract
Identifying an active lead molecule, selecting a viable drug candidate and developing a marketable product are profoundly influenced by molecular properties and dosage form design. This chapter discusses the importance of a molecule's physicochemical properties and the link with oral dosage form design strategies. The Biopharmaceutics Classification Scheme (BCS) is used to identify oral dosage form options that have the best chance of overcoming drug delivery problems. Physicochemical characterization not only can guide the selection of formulation strategies but also, if incorporated into the lead selection process, can influence analog selection and lead optimization. The end result of considering physicochemical properties is to reduce the risk of failure by facilitating the identification of appropriate dosage form design options and, at the same time, allow discovery chemists to maximize chances of identifying commercially viable leads.
SyntheticDNA‐Targeted Chemotherapeutic Agents And Related Tumor‐Activated Prodrugs
Authors: Denny William A. 
Published: September 2010

AbstractSynthetic drugs have always played an important role in cancer therapy. The first systemic anticancer drugs were synthetic DNA alkylating agents and DNA antimetabolites. The original antimetabolites such as cytosine arabinoside and 5‐fluorouracil have been augmented by more recent compounds such as gemcitabine, fludarabine, cladribine, and pentostatin, which inhibit DNA polymerase action during DNA synthesis. A new development is the related compounds deazacytidine and decitabine, which inhibit reactivate silenced genes by inhibition of cytosine methylation. Nitrogen mustards, platinum complexes, nitrosoureas, and triazene‐based DNA‐methylating agents are direct DNA‐modifying agents that still play an important role in clinical treatment. Methotrexate and more recent lipophilic analogs, together with older drugs such as 5‐fluorouracil, are used as inhibitors of different enzymes in the folate pathway necessary for the synthesis of pyrimidine nucleotides. The potent activity of natural products such as doxorubicin also led to the development of the synthetic topoisomerase inhibitors that are now another important group of drugs whose therapeutic effects are due to enzyme‐mediated DNA modification. Finally, an increasing understanding of tumor physiology and genetics has allowed the development of tumor‐activated prodrugs of DNA‐active agents. Using hypoxia, gene therapy or antibody targeting to activate such prodrugs specifically in tumor tissue has the potential to increase the therapeutic index of these agents by limiting the exposure of sensitive nontumor cell populations.
Medicinal Chemistry Approaches for Multitarget Drugs
Authors: Morphy Richard , Rankovic Zoran 
Published: September 2010

AbstractIt has become increasingly well recognized that modulating multiple biological targets in parallel can be beneficial for treating diseases with complex etiologies such as cancer, asthma, and psychiatric diseases. Both screening and knowledge‐based strategies have been used for generating ligands with a specific multitarget profile (designed multiple ligands or DMLs). DML projects are often challenging for medicinal chemists, with the need to appropriately balance affinity for two or more targets while obtaining physicochemical and pharmacokinetic properties that are consistent with the administration of an oral drug. The physicochemical properties of DMLs are influenced to a large extent by the proteomic superfamily to which the targets belong and the lead generation strategy that is pursued. Since DML projects are resource hungry, an early assessment of the feasibility of any given DML project is essential.
Protein–Protein Interactions as Drug Discovery Targets
Authors: Dömling Alexander 
Published: September 2010

AbstractProtein–protein interactions (PPIs) recently have been recognized as a major class of drug targets. Many of the successful “classical” biotechnology protein drugs are agonists or antagonists of PPIs and there are established pathways for their development. However, small molecular weight compounds as antagonists of PPIs still pose a major problem to discovery due to the inherent physicochemical properties of their targets. Recently, several small molecular weight antagonists of PPIs advanced into clinical trials and thus comprise a proof‐of‐concept to this young area in medicinal chemistry. This chapter summarizes the area of small molecular weight antagonists of PPIs with a focus on recent success stories. After a short introduction into the structural biology of PPIs, recognized important PPI targets, discovery pathways of their inhibitors are discussed. The PPI p53‐Mdm2 with potential applications in cancer is used as a case study to demonstrate to diversity of approaches leading to many different lead structures. In contrast, the discovery of IL‐2/IL‐2 rec. antagonists is discussed to highlight adaptive high affinity binding to hotspot regions.
QM
and
QM
/
MM
Approaches to Evaluating Binding Affinities
Authors: Shaw Katherine E. , Woods Christopher J. , Mulholland Adrian J. 
Published: September 2010

Abstract
Binding free energy predictions have the potential to play pivotal roles in the drug discovery process, ranging from aiding selection of hit molecules from large databases of compounds to optimizing lead structures. Calculation of relative binding free energies from molecular simulations (e.g., molecular dynamics or Monte Carlo simulations), though computationally intensive, have proved their worth in a number of pharmaceutical applications. Despite this, it is now clear that, in many cases, the methods typically used in such simulations to model molecular interactions have significant limitations. For example, in protein–ligand systems in which charge transfer or polarization are important, or where a metal ion is present in the binding site, conventional molecular mechanics (MM) methods may not represent binding accurately. Methods based on quantum mechanics (QM), for all or part of the system, are potentially more accurate. This chapter reviews recent advances in the growing field of calculating or predicting binding free energies using a quantum mechanical (i.e., quantum chemical, electronic structure) treatment of all or part of the system, for example, a QM description of the ligand alone (or with part of the binding site), coupled to a MM treatment of the protein (QM/MM calculations) or a QM description of the entire protein–ligand complex.
Pharmacophores
Authors: Martin Yvonne C. 
Published: September 2010

AbstractA pharmacophore is a hypothesis of the 3D shape and electrostatic features that a molecule must possess in order to have a particular biological activity. The hypothesis may derive either from the 3D structure of a macromolecule–ligand complex or from the structure–activity relationships of ligands. The contribution briefly describes how the pharmacophores are generated. Tables, each with more than 30 examples, summarize the results of the application of ligand‐based and structure‐based methods to the identification of novel biologically active compounds during 2006–2008.
Protein Flexibility in
In Silico
Screening
Authors: Gohlke Holger , Kopitz Hannes 
Published: September 2010

Abstract

We summarize computational approaches in structure‐based ligand design (SBLD) and
in silico
screening that address issues of protein flexibility and mobility. In particular, we consider how protein plasticity can be incorporated into docking strategies. As a first requirement, one needs to detect what can move and how. Moving protein parts can be identified from experimental information as well as established computational techniques such as molecular dynamics (MD) simulations, graph theoretical and geometry‐based approaches, or harmonic analysis‐based methods. Second, this knowledge needs to be transformed into a docking algorithm. A multitude of approaches considering protein mobility has been introduced recently, with motions modeled either implicitly or explicitly. In the latter case, one can further distinguish between modeling of side‐chain‐only motions and motions including backbone changes. In all cases, accuracy needs to be balanced against efficiency. Case studies for which the inclusion of protein plasticity was crucial to success are noted along these lines. This allows us to identify scope and limitations of the current approaches, as well as guidelines for further developments.
Cost‐Effectiveness Analyses Throughout the Drug Development Life Cycle
Authors: Arnold Renée J.G. 
Published: September 2010

AbstractCost‐effectiveness analysis (CEA) is a systematic, quantitative method for summarizing health benefits and health resources of various treatment options into single numbers or ratios so that policy makers can choose among them. Computer modeling of cost‐effectiveness may play a significant role in informing the pharmaceutical decision‐making process throughout a product's life cycle, increasing the likelihood of reimbursement and broad use.
The Role of Permeability in DrugADME/PK, Interactions and Toxicity, and the Permeability‐Based Classification System (PCS)
Authors: Fagerholm Urban 
Published: September 2010

AbstractPermeability (Pe) is one of the key determinants in the absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK) of drugs and their metabolites. Predictions of ADME/PK, interactions, elimination routes, exposures, and toxicity require, therefore, that the role of permeability in different organs is considered, investigated and understood. That includes studies of and knowledge about the relation betweenPeand fraction absorbed (fa) (or fraction reabsorbed;fra) in various organs, and the interplay between passive permeability and active permeability, metabolism and solubility/dissolution. Relationships between passivePeandfain the human intestine, liver, renal tubuli (fra), and brain have been established, and these are the basis of the Permeability‐Based Classification System (PCS). This system demonstrates sigmoidalPeversusfaandfrarelationships of different shapes and shifts, and is divided into four permeability categories (very high/high/intermediate/low). Results show or indicate that the liver and brain have comparably high intrinsic passive uptake capacities, metabolism (rather than uptake, diffusion, and dissociation) is the general rate‐limiting step in hepatic metabolic clearance (CLH), and few high permeability compounds have dissolution‐limited gastrointestinalfa. Active transport processes contribute to the intestinal and hepatic uptake, and renal, biliary, and intestinal drug excretion, of many drugs with limited passivePe. Active transport could be clinically relevant for brain uptake of both low and high passive permeability compounds. Related drug–drug interactions and polymorphism appear most pronounced for drugs actively absorbed and excreted by the liver. Combined with intrinsic metabolic CL data, the PCS is useful for predictions of CLH, renal and biliary excretion potential, gut‐wall extraction ratio, oral bioavailability and effects of polymorphism, and for assessment of potential drug–drug or drug–metabolite interactions, and drug and metabolite organ/cell trapping.
Crystallographic Survey of Albumin Drug Interaction and Preliminary Applications in Cancer Chemotherapy
Authors: Carter Daniel C. 
Published: September 2010

Abstract
An overview of the results of a comprehensive crystallographic structural survey of drug binding to human albumin at atomic resolution is presented. More than 350 complexes were examined, ultimately producing more than 200 structures with representatives in every major therapeutic category. The survey indicated 12 independent drug‐binding locations dominated by the three sites located within subdomains IIA, IIIA, and IB. Site IB, the most structurally accommodating site on albumin, revealed a propensity for large heterocyclic ligands and showed the highest overall binding frequency at 49%. Details of IB ligand‐binding chemistry are presented for several ligands including the camptothecin, anthracyclin, and podophylotoxin families of oncology drugs. The results from the survey were used to establish a therapeutic drug combination approach that favorably alters the albumin‐based pharmacokinetics of several highly cytotoxic oncology drugs leading to marked improvements in safety and efficacy. Examples are presented for selected applications of improving the albumin‐based pharmacokinetics of this information in drug development to improving the safety and efficacy of highly cytotoxic drugs for several important families of oncology drugs.
Nanotechnology in Drug Delivery
Authors: Uchegbu Ijeoma F. , Schatzlein Andreas G. 
Published: September 2010

AbstractNanotechnology involves manipulating matter at the nanoscale (<1000 nm); that is, manipulations at less than thousandth of a millimeter, and for drug delivery applications this typically takes the form of creating nanoparticles (5 ∼ 800 nm) that are then used to package drug molecules and genes. By packaging pharmacologically active compounds within nanoparticles, nanomedicines are created. It is possible to control drug biodistribution and achieve therapeutic benefit with these nanomedicines. This chapter outlines the various chemistries and nanomedicine preparation strategies that have been used to produce nanoparticles and highlights the drug delivery benefits that are achievable from these nanoscale arrangements. The chemical compounds used to construct these nanomedicines are as follows: low molecular weight self‐assembling amphiphiles, self‐assembling amphiphilic polymers, polymer–drug conjugates, water insoluble polymers/cross‐linked polymers, dendrimers, and carbon nanotubes. Engineering of these particles has produced nanomedicines that target drugs and genes to tumors and improve the brain delivery of peptides and other molecules. These particles are also capable of promoting oral drug absorption and drug transport across other biological barriers such as the cornea and the skin. Only a few of these technologies are commercially available presently, such as liposomes (e.g., Doxil®), low molecular weight micelles (e.g., Fungizone®), and polymer–drug conjugates (Oncaspar®); but the therapeutic benefits being observed in both preclinical studies and early clinical testing suggest that more of these technologies will emerge into the patient arena in the future.
Antiplatelet Agents
Authors: Chackalamannil Samuel 
Published: September 2010

AbstractIn addition to their life‐sustaining role in hemostasis and wound healing, platelets play a central role in the pathogenesis of coronary artery, cerebrovascular, and peripheral vascular diseases. Under pathologic conditions such as rupture of an atherosclerotic plaque, the platelet activation mechanism and coagulation mechanism synergize in the formation of an occlusive thrombus leading to ischemic disorders such as acute coronary syndrome and stroke. Antiplatelet agents are the mainstay of pharmacological approach for the treatment of ischemic vascular disorders. Platelets have multiple cell‐surface receptors that, upon activation by specific ligands, trigger a cascade of cellular events resulting in the activation of the integrin glycoprotein (GP) IIb/IIIa receptors. Activated GP IIb/IIIa receptors cross‐link with fibrinogen causing platelet to aggregate. Aggregated platelets get trapped by fibrin meshwork, produced by the proteolysis of fibrinogen by thrombin. Cell‐surface platelet receptors have been the target of antiplatelet therapy. For example, aspirin, the most widely used antiplatelet agent, inhibit the biosynthesis of thromboxane A2, the endogenous agonist that activates thromboxane receptors. The ADP antagonists such as clopidogrel and ticlopidine inhibit ADP‐mediated activation of purinergic P2Y12receptors. Glycoprotein IIb/IIIa antagonists such as abciximab, eptifibatide, and tirofiban inhibit GP IIb/IIIa receptors, which involve the final common pathway of platelet aggregation. Phosphodiesterase inhibitors are less widely used antiplatelet agents that potentiate intracellular cyclic AMP levels. Promising newer antiplatelet agents such as thrombin receptor antagonists with reduced bleeding liability, third‐generation thienopyridine ADP antagonists with improved potency and reversible ADP antagonists are at advanced stage of development.
Atherosclerosis
II
:
HDL
Elevation
Authors: Ali Amjad , Hunt Julianne A. , Sinclair Peter J. 
Published: September 2010

Abstract
Atherosclerosis is an arterial disease associated with elevated plasma lipid levels and is a major cause of morbidity and mortality worldwide. Clinical trials have demonstrated that reduction of low‐density lipoprotein cholesterol (LDL‐C), as can be accomplished with HMG‐CoA reductase inhibitors (statins), leads to a reduction in coronary events and mortality by about 25%. Conversely, epidemiological evidence indicates that high‐density lipoprotein cholesterol (HDL‐C) levels have an inverse correlation with risk of coronary artery disease. The beneficial effects of HDL have been attributed to its involvement in the movement of cholesterol from the periphery to the liver as well as to its apparent antioxidant and anti‐inflammatory activities. Consequently, there is much interest in identifying therapeutic approaches to raising HDL that will be useful as a treatment for atherosclerosis and dyslipidemias. The properties and physiologic role of HDL, as well as approaches to increasing plasma HDL concentrations, will be summarized.
Drug Discovery in Non‐Life‐Threatening Disorders: Erectile Dysfunction, Insomnia, and Smoking Cessation
Authors: Rotella David P. 
Published: September 2010

AbstractDrug discovery for non‐life‐threatening disorders is an active area of medicinal chemistry research. This chapter will describe the discovery and properties of phosphodiesterase 5 inhibitors for erectile dysfunction, the medicinal chemistry of agents for treatment of insomnia, and smoking cessation.
Immunosuppressive Agents for the Prevention of Transplantation Rejection
Authors: Pitts William J. 
Published: September 2010

AbstractThis chapter will focus on “small” molecule therapeutics that demonstrate useful immunosuppressant activity including established classes such as calcineurin inhibitors (cyclosporin A and tacrolimus),mTOR(mammaliantargetofrapamycin) agents (sirolimus, everolimus), and antiproliferative/antimetabolite agents (azathioprine, mycophenolic acid derivatives). This chapter will also introduce some agents with newer pharmacology mechanisms such as sphingosine receptor modulation (FTY720), inhibition of JAK3 (CP‐690,550), and inhibition of PKC θ (AEB071). Other agents useful in organ transplantation including glucocorticoids (such as prednisone and dexamethasone), nitrogen mustards (such as cyclophosphamide), and biologic agents (such as muromonab‐CD3, basiliximab, and daclizumab) are discussed elsewhere.