Accomplishments and challenges in integrating software for computer-aided ligand design in drug discovery

Summary No one commercial vendor of molecular modeling tools supplies all the capabilities needed for computer-assisted molecular design. Integration of software from different sources provides the user with both unique capabilities and productivity improvements. Recent examples of new capabilities are 3D database searching, automated pharmacophore matching, and computer-assisted de novo design. Productivity enhancements result from storing 3D coordinates in a chemical information database, from using 3D database searching programs and from integrating substructure recognition algorithms into molecular graphics and file format conversion programs. Integration of software is hampered by continual changes in the software platforms and the lack of toolkit programming interfaces to much of the software.     

全新药物设计方法与常用软件及其在抗癌药物设计中的应用

计算机辅助药物设计已普遍应用于药物研发过程,大大加快了药物开发的速度.特别是全新药物设计方法可以用于识别作用于特异性靶点的全新配体结构.全新药物设计常用软件有LUDI,LigBuilder,LeapFrog,SPROUT和SYNOPSIS等,常用方法有片段连接、片段生长、侧链替换和骨架跃迁等.全新药物设计方法在一些抗癌化合物,如纺锤体驱动蛋白抑制剂、血管内皮生长因子抑制剂、亲环蛋白A抑制剂和BRAF抑制剂等的发现方面,已经发挥了重要作用.综述全新药物设计方法与常用软件,并举例讨论其在新型抗癌药物领域中的应用.     

Recent developments with boron as a platform for novel drug design

ABSTRACT

Introduction: After decades of development, the medicinal chemistry of compounds that contain a single boron atom has matured to the present status of having equal rights with other branches of drug discovery, although it remains a relative newcomer. In contrast, the medicinal chemistry of boron clusters is less advanced, but it is expanding and may soon become a productive area of drug discovery.

Areas covered: The author reviews the current developments of medicinal chemistry of boron and its applications in drug design. First generation boron drugs that bear a single boron atom and second generation boron drugs that utilize boron clusters as pharmacophores or modulators of bioactive molecules are discussed. The advantages and gaps in our current understanding of boron medicinal chemistry, with a special focus on boron clusters, are highlighted.

Expert opinion: Boron is not a panacea for every drug discovery problem, but there is a good chance that it will become a useful addition to the medicinal chemistry tool box. The present status of boron resembles the medicinal chemistry status of fluorine three decades ago; indeed, currently, approximately 20% of pharmaceuticals on the market contain fluorine. The fact that novel boron compounds, especially those based on abiotic polyhedral boron hydrides, are currently unfamiliar could be advantageous because organisms may be less prone to developing resistance against boron cluster-based drugs.     

The cyclotides: novel macrocyclic peptides as scaffolds in drug design

Cyclotides are a novel class of circular, disulfide-rich peptides (approximately 30 amino acids) that display a broad range of bioactivities and have exceptionally high stability. Their physical properties, which include resistance to thermal and enzymatic degradation, can be attributed to their unique cyclic backbone and knotted arrangement of disulfide bonds. The applicability of linear peptides as drugs is potentially limited by their susceptibility to proteolytic cleavage and poor bioavailability. Such limitations may be overcome by using the cyclotide framework as a scaffold onto which new activities may be engineered. The potential use of cyclotides for drug design is evaluated here, with reference to rapidly increasing knowledge of natural cyclotides and the emergence of new techniques in peptide engineering.     

Allosteric regulators of the proteasome: potential drugs and a novel approach for drug design

The proteasome recently gained an exceptional attention as a novel drug target, therefore its inhibitors became important subjects for rational drug design. A synthetic competitive inhibitor Velcade was lately approved in a fast-track process to treat multiple myeloma and is tested with other types of cancers. The proteasome is a major proteolytic assembly in eukaryotic cells responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and apoptosis. The ubiquitin-proteasome pathway has been implicated in many diseases such as cancer, autoimmune diseases, inflammation, and stroke. The activity of the proteasome can be blocked for therapeutic purposes with competitive inhibitors like Velcade, which trigger apoptosis in target cells. However, much more versatile outcomes and a true control of the proteasome can be achieved with allosteric regulators. Certain natural proteins and peptides bind to the catalytic core of the proteasome and allosterically induce a wide array of effects ranging from changes in product size to substrate-specific inhibition. Designing small synthetic compounds allosterically interacting with the proteasome represents a novel approach that has enormous potential for the treatment of a wide range of diseases. Below we provide a review of current knowledge about proteasomal allosteric ligands.     

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。     

治疗失眠症新药雷美替胺

雷美替胺（ramelteon）通过选择性激动褪黑激素MT1和MT2受体，用于治疗难以入睡型失眠症。研究表明：其能有效地缩短入睡时间。提高总睡眠时间和入睡效率，且使用安全，无严重药物不良反应．长期用药不会产生滥用或药物依赖性，现对该药的药理学、药效学及临床应用等进行综述。     

Developing G-quartet oligonucleotides as novel anti-HIV agents: focus on anti-HIV drug design

Recently, a new class of oligonucleotides, forming G-quartet structures, has been developed as novel anti-HIV agents. Several critical structure-activity relationships between HIV-1 integrase and G-quartet oligonucleotides have been demonstrated. In addition the mechanism of the inhibition of HIV-1 integrase by G-quartet oligonucleotides, such as T30695 and its derivatives, has been explored. This review summarises the preliminary studies of developing G-quartet oligonucleotides as novel anti-HIV agents in several aspects including structure-activity relationship, stability-activity correlation, mechanism of HIV-1 integrase inhibition, substitution of phosphorothioates and targeting HIV-1 integrase in infected cells, which, hopefully, could help for developing a novel, efficient anti-HIV agent.     

Developing G-quartet oligonucleotides as novel anti-HIV agents: focus on anti-HIV drug design

Recently, a new class of oligonucleotides, forming G-quartet structures, has been developed as novel anti-HIV agents. Several critical structure-activity relationships between HIV-1 integrase and G-quartet oligonucleotides have been demonstrated. In addition the mechanism of the inhibition of HIV-1 integrase by G-quartet oligonucleotides, such as T30695 and its derivatives, has been explored. This review summarises the preliminary studies of developing G-quartet oligonucleotides as novel anti-HIV agents in several aspects including structure-activity relationship, stability-activity correlation, mechanism of HIV-1 integrase inhibition, substitution of phosphorothioates and targeting HIV-1 integrase in infected cells, which, hopefully, could help for developing a novel, efficient anti-HIV agent.     

龙利叶抗炎镇痛作用研究

3, 6-脱水己糖是一种独特而重要的糖类物质。在某些天然产物以及化学合成活性小分子中因有3, 6-脱水己糖片段的存在而使其具有特殊的物理化学性质以及生物活性,因此化学家研究了不同方法来构建3, 6-脱水己糖结构。主要介绍近年来3, 6-脱水己糖的构建方法及其在类似结构化合物合成上的运用,为研究者在合成此类化合物时提供参考。

     

Glycobiology: a growing field for drug design

Recent information on protein-carbohydrate interactions in physiological and pathological situations substantiates the intuitive belief in carbohydrates as candidates for drug design. Most noteworthy, short saccharide sequences have been shown to be specific receptors for adhesion of circulating leukocytes to vascular endothelial cells, a phenomenon induced at local inflammatory sites. There is strong evidence that mammalian sperm cells carry proteins that interact specifically with saccharide receptors on eggs. The influenza virus receptor on animal cells, sialic acid, has been analysed in the crystal conformation as a complex with the viral receptor-binding protein. These and other convincing examples discussed here by Karl-Anders Karlsson will inspire new approaches to the treatment of several important medical conditions where existing methods are insufficient.     

The case for open-source software in drug discovery

Widespread adoption of open-source software for network infrastructure, web servers, code development, and operating systems leads one to ask how far it can go. Will "open source" spread broadly, or will it be restricted to niches frequented by hopeful hobbyists and midnight hackers? Here we identify reasons for the success of open-source software and predict how consumers in drug discovery will benefit from new open-source products that address their needs with increased flexibility and in ways complementary to proprietary options.     

Targeted lipid based drug conjugates: a novel strategy for drug delivery

A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically toward cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [(3)H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs toward SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 μM) and B-12HS-ACV (23.99 ± 3.20 μM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 μM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [(3)H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [(3)H] biotin permeability in the presence of biotin and biotinylated prodrugs, further indicating a carrier mediated translocation by SMVT. Overall, results from these studies clearly suggest that these biotinylated lipid prodrugs of ACV possess enhanced affinity towards SMVT. These prodrugs appear to be potential candidates for the treatment of oral and ocular herpes virus infections, because of higher expression of SMVT on intestinal and corneal epithelial cells. In conclusion we hypothesize that our novel prodrug design strategy may help in higher absorption of hydrophilic parent drug. Moreover, this novel prodrug design can result in higher cell permeability of hydrophilic therapeutics such as genes, siRNA, antisense RNA, DNA, oligonucleotides, peptides and proteins.     

LEA3D: a computer-aided ligand design for structure-based drug design

We present an improved version of the program LEA developed to design organic molecules. Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a tool for the investigation of such problems. New software, called LEA3D, is now able to conceive organic molecules by combining 3D fragments. Fragments were extracted from both biological compounds and known drugs. A fitness function guides the search process in optimizing the molecules toward an optimal value of the properties. The fitness function is build up by combining several independent property evaluations, including the score provided by the FlexX docking program. One application in de novo drug design is described. The example makes use of the structure of Mycobacterium tuberculosis thymidine monophosphate kinase to generate analogues of one of its natural substrates. Among 22 tested compounds, 17 show inhibitory activity in the micromolar range.