History and evolution of the pharmacophore concept in computer-aided drug design

With computer-aided drug design established as an integral part of the lead discovery and optimization process, pharmacophores have become a focal point for conceptualizing and understanding receptor-ligand interactions. In the structure-based design process, pharmacophores can be used to align molecules based on the three-dimensional arrangement of chemical features or to develop predictive models (e.g., 3D-QSAR) that correlate with the experimental activities of a given training set. Pharmacophores can be also used as search queries for retrieving potential leads from structural databases, for designing molecules with specific desired attributes, or as fingerprints for assessing similarity and diversity of molecules. This review article presents a historical perspective on the evolution and use of the pharmacophore concept in the pharmaceutical, biotechnology, and fragrances industry with published examples of how the technology has contributed and advanced the field.     

Drug treatments for subjective tinnitus: serendipitous discovery versus rational drug design

Progress has been made in understanding the neural basis of subjective tinnitus (ST); however, this has not, as yet, translated into many new drug treatments. One reason for this is that realistic behavioral models of ST in animals have been developed only recently, and are still not widely used. Nonetheless, some significant pharmacological advances have been made. At present, there is evidence to support the efficacy of transtympanic gentamicin administration in the treatment of tinnitus associated with Meniere's disease; there is also some evidence to support the efficacy of intratympanic steroid and lidocaine application in the management of ST. Although benzodiazepines and anti-epileptic drugs appear to be effective in many cases of this condition, there is concern about their adverse side effect profile. Based on well-controlled clinical trials, vasodilators such as misoprostol, and histamine receptor ligands should be further investigated. Finally, given the evidence that ST is a form of sensory epilepsy, new antiepileptic drugs should be tested for potential efficacy as they are developed; such drugs may include novel N-methyl-D-aspartate receptor antagonists, as well as cannabinoids.     

Quantitative design of drug compatibility by weighted modification method.

AIM: To set up a new method for designing and quantitatively analyzing drug compatibility. METHODS: Drugs for compatibility were divided into 6 dose levels which were evenly distributed to 6 compound groups according to a fixed design. A new mathematical model was set up to fit the dose-effect data of 6 groups. The coefficients, obtained from the model, reflected the dose-effect relationship and the important degree of every drug in combination. According to the coefficients, the drugs in compatibility could be distinguished into principal drug, synergist, inferior, antagonist, and assistant. Because compatibility in the maximal effect group was nearly (or was) an optimal one in 6 groups, the doses in the group were taken as a base for further modification which considered interaction among drugs. The results of the modification were demonstrated by further experiment. This method was applied to design and to quantitatively analyze the compatibility of allantoin, metronidazole, and dexamethasone sodium phosphate by 2 effect indices in mice. RESULTS: This new method was able to effectively determine important degree of drugs in combination, and to optimize their doses for designing compatibility. CONCLUSION: This weighted modification method is a highly efficient, accurate, and practical means for designing and quantitatively analyzing drug compatibility.     

Ibritumomab: new drug. Interesting concept, disappointing in practice

(1) First-line standard chemotherapy for follicular non-Hodgkin's lymphoma is based on alkylating agents. For patients who relapse, rituximab, a monoclonal antibody targeting CD20 receptors on tumour cells, induces remissions lasting at least 9 months in about 50% of cases. However, the infusions are often poorly tolerated and reactions can be severe. (2) Ibritumomab is a monoclonal antibody similar to rituximab. It is not in itself cytotoxic. Yttrium-90-radiolabeled ibritumomab has been licensed in the EU since 2004 for local tumour radiotherapy, administered shortly after rituximab therapy. It is approved as a third-line treatment for follicular lymphoma, after rituximab failure. (3) The only available comparative trial, lasting 4 years, involved 143 patients who were treated either with rituximab followed by radiolabeled ibritumomab, or with rituximab alone. The sequential treatment yielded more tumour responses but the time to lymphoma progression and clinical outcomes did not differ between the two treatment groups. (4) In a non comparative trial about half the patients in whom rituximab had failed responded to rituximab + radiolabeled ibritumomab, but lymphoma progression occurred after a median of only 7 months. (5) Patients who receive sequential therapy with rituximab + ibritumomab are exposed to the adverse effects of rituximab plus supplementary gastrointestinal, respiratory, haematological and infectious risks, mainly due to persistent myelosuppression. (6) The radiation hazard for the patient (irradiation of healthy organs) and for the environment appears to be limited, because of the short reach of beta particle emission (5 mm) and the short half-life of yttrium 90 (2.7 days). (7) Yttrium 90 radiolabeling requires special equipment and specialised personnel working in an approved centre, which can restrict access to treatment. (8) Radiolabeled ibritumomab appears to have a negative risk-benefit balance, and should only be used in clinical trials.     

Parachors in drug design.

Parachor has been used extensively in physical organic chemistry for structure determination. It has rarely been used as a parameter for the correlation of structure and biological activity. We have reexamined the parachor concept for structure-activity correlations of some closely related analogs. Parachor is an additive and constitutive molecular parameter consisting of two physical properties, molar volume and surface tension, factors which appear to be important in the passage of a drug or hormone from the site of administration or synthesis to the site of action. Correlations between parachor values and biological activities for a number of drug classes have been examined. Good correlations were obtained for three classes: thyromimetic activity of 3'-substituted thyroxine analogs, blood clotting inhibitory activity of 5-substituted pentylamines, and local anesthetic activity of the paracaines. Correlations with parachor are comparable to those obtained with the Hansch hydrophobic constant π for six more drug classes: antibiotic activity of penicillins; fibrinolytic activity of 2,4-substituted benzole acids; parasympatholytic activity of 2-alkyl-diphenhydramines; beta-receptor activity of sympathomimetics; fibrinolytic activity of 5-substituted salicylic acids; and isohemolytic concentrations for n-alcohols. The relative merits of parachor and partition coefficients in predicting biological activities are discussed. When data are available for both parameters, both correlations appear to be equally useful. Because the parachor is a truly additive and constitutive property and involves no new experimental measurements, its predictive usefulness in drug design deserves further evaluation.     

Drug delivery systems. 1. site-specific drug delivery using liposomes as carriers

Drug delivery systems, offering controlled delivery of biologically active agents, are rapidly gaining importance in pharmaceutical research and development. To achieve controlled drug delivery, i.e., the administration of drugs so that optimal amount reaches the target site to cure or control the disease state, increasingly sophisticated systems containing different carriers have been developed. Macromolecules represent one of the carriers involved, and they have taken on a significantly prominent role in various modes of administration of therapeutic agents. Among macromolecules, for example, synthetic copolymers, polysaccharides, liposomes, polyanions and antibodies, as drug carriers, liposomes have proved most effective for diseases affecting the reticuloendothelial system and blood cells in particular. Liposomes, which are vesicles consisting of one or more concentrically ordered assemblies of phospholipids bilayers, range in size from a nanometer to several micrometers. Phospholipids such as egg phosphatidylcholine, phosphatidylserine, synthetic dipalmitoyl-DL-alpha-phosphatidylcholine or phosphatidylinositol, have been used in conjunction with cholesterol and positively or negatively charged amphiphiles such as stearylamine or phosphatidic acid. Alteration of surface charge has been shown to enhance drug incorporation and also influence drug release. Because of the multifold characteristics as drug carriers, liposomes have been investigated extensively as carriers of anticancer agents for the past several years. Liposomal entrapments include a variety of pharmacologically active compounds such as antimalarial, antiviral, anti-inflammatory and anti-fungal agents as well as antibiotics, prostaglandins, steroids and bronchodilators to name a few. The liposomal entrapment has been shown to have considerable effect on the pharmacokinetics and tissue distribution of administered drugs. Despite the potential value of liposomes as unique carriers, the major obstacles are the first order targeting of a systemically given liposomes, physical stability and manufacture of the liposomal products and these problems still remain to be overcome. Drug delivery systems evolving in the 1980s have become increasingly dependent on fundamental cell-biology and receptor-mediated endocytotic mechanisms. Drug delivery systems during the 1990s may take advantage of the specificity of receptor-mediated uptake mechanisms as well as polymer chemistry and cell-biology in order to introduce more precise and efficient target-specific delivery systems that are based especially on the liposome technology.     

药物分子设计的策略：双靶标药物设计

新药研究可分两种模式：以生理学和表型为基础的研究和以生物靶标为核心的药物研究,这两种模式相互补充和印证。当今以靶标为切入点的模式占主导地位,研发出不少新药。许多疾病如肿瘤、代谢性和中枢神经系统疾病的药物治疗非单一靶标可治愈,同时干预与疾病相关的双（多）靶标药物可提高药物的效力,因而成为创制新药的活跃领域。双靶标药物可以是两个受体的调节剂、两个酶的抑制剂或同时作用于酶和受体或作用于受体和通道或转运蛋白的双功能性分子等。从药物分子设计的视角,构建双靶标药物分子可将两个活性分子或其药效团用连接基连接在一起,构成连接型分子;两个活性分子的部分结构或药效团特征相同,可将共同部分融合或并合,形成融合型或并合型分子,可以控制分子的大小和相对分子质量,使得分子结构的药效空间与药代动力学空间有较大的重叠,提高成药的几率。     

Privileged structures: a useful concept for the rational design of new lead drug candidates

Privileged structures are defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications. In the present work, we describe some examples and applications of the usefulness of the privileged structure concept for the structural design of new drug candidates, by discussing the eligibility of such motifs, including the identification of the N-acylhydrazone template as privileged structures.     

基于QbD理念的药品质量分析研究新概念

本文阐述质量源于设计理念在药品质量评价分析中的应用基础,结合2010年全国评价性抽验的成效及特点,诠释质量源于设计理念在药品质量评价分析中的应用实践,展望质量源于设计理念在药品抽验工作计划、质量分析、质量再评价研究中的应用前景。     

A manual method for applying the Hansch approach to drug design.

A procedure is described in which an initial small group of compounds is selected, tested, and ordered according to potency. The potency order in the group is then compared to the tabulated potency order calculated for various parameter dependencies relating to hydrophobic, electronic, and steric effects. From this activity pattern analysis the probable operative parameters can be deduced and a new substituent selection made for the synthesis of potentially more potent analogues. Application of the method is illustrated with a series of examples. It differs from a previously described decision tree, single compound stepwise approach in that it involves the batchwise analysis of small groups of compounds, usually the preferred procedure for logistical reasons if the compounds are relatively easy to synthesize.     

Drug therapy reviews: drug therapy of status epilepticus.

Drug treatment of status epilepticus is reviewed. Tonic-clonic, focal motor, complex partial and absence status epilepticus are discussed. In managing tonic-clonic status epilepticus one should: (1) maintain vital functions at all times, (2) identify and treat precipitating factors and (3) administer an intravenous loading dose of phenytoin sodium or phenobarbital sodium. Careful use of i.v. diazepam sometimes helps to achieve these objectives. Intravenous phenytoin sodium and phenobarbital sodium provide definitive, long-term control of tonic-clonic seizures but must be administered slowly and require time to reach peak brain concentrations. Intravenous diazepam appears to enter and exit from the brain rapidly and may control seizures while therapeutic brain concentrations of long-acting drugs are being achieved. Phenytoin, phenobarbital and diazepam should not be administered intramuscularly in treating status epilepticus. Treatment of focal motor and complex partial status epilepticus is similar to that of tonic-clonic status epilepticus, but i.v. diazepam is required less frequently and loading doses of phenytoin and phenobarbital sometimes can be given more slowly. Status epilepticus of the absence type is managed with i.v. acetazolamide sodium or diazepam. Paraldehyde, muscle relaxants, general anesthesia and lidocaine may be tried when conventional therapies fail.