Mini Reviews in Medicinal Chemistry - Volume 12, Issue 10, 2012

This special issue of the journal of MRMC is dedicated to Dr. Atta-ur-Rahman on the occasion of his 70th birthday and in recognition of his many outstanding contributions to Organic Chemistry. Prof. Rahman's honors include: the first scientist from the Muslim world to have won the prestigious UNESCO Science Prize (1999) in the 35 year old history of the Prize; elected as Fellow of Royal Society (London) in July 2006; conferred honorary doctorate degrees from many prestigious universities, including the University of Cambridge. On a national level his services are acknowledged in the form of four prestigious civil awards, including these highest national awards: Nishan-e-Imtiaz (2002), Hilal-e-Imtiaz (1998), Sitara-e- Imtiaz (1991) and Tamgha-e-Imtiaz (1983). He is currently the Editor-in-Chief of 12 scientific journals in fields ranging from Medicinal Chemistry to Pharmaceutical Drug Design. Seventy six students have completed their Ph.D. degrees under his supervision. He chairs the Network of Academies of Sciences of Islamic Countries (NASIC) and is the Vice-President (Central & South Asia) of the Academy of Sciences for the Developing World (TWAS) Council, and Foreign Fellow of Korean Academy of Sciences. Prof. Atta-ur-Rahman was the President of the Pakistan Academy of Sciences (2003-2006) and was again elected as the President of the Academy from 1st of January 2011. In particular, Prof. Rahman has made outstanding contribution to Mini-Reviews in Medicinal Chemistry. He has over 852 Publications in leading International journals in several fields of organic chemistry including 662 research publications, 18 patents, 114 books and 59 chapters in books published by major U.S. and European presses. The contributions of Prof. Rahman to the uplifting of science in Pakistan in his capacity as the Federal Minister for Science & Technology and later as Chairman Higher Education Commission were acknowledged by a civil award of the government of Austria and TWAS prize for institution building as well as by four editorials in Nature. We congratulate Dr. Atta-ur-Rahman on his 70th Birthday and wish him health, prosperity, and a long, active and successful future in his favorite pursuit---organic chemistry and inspiring scientific accomplishment. With best wishes

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The role of monoamine oxidase (MAO) inhibitors has expanded in the PD treatment. The present review will summarize the current structureactivity relationship information available on MAOs inhibitors of unrelated families of compounds of oxygen heterocyclic type based on coumarin, chromone and chalcone scaffolds. As the current hitting-one-target therapeutic strategy has been proved to be quite inefficient in PD, this review will also discuss about the development of multi-target drugs, in which MAO inhibition plays a counter-part, as a novel and promising treatment approach for PD.

The adjustment of multiple criteria in hit-to-lead identification and lead optimization is a major advance in drug discovery. Thus, the development of approaches able to handle additional criteria for the early simultaneous treatment of the most important properties determining the pharmaceutical profile of a drug candidate is an emergent issue in this area. In this paper, we review a desirability-based multi-objective QSAR method allowing the joint handling of multiple properties of interest in drug discovery: the MOOP-DESIRE methodology. This methodology adapts desirability theory concepts allowing the holistic modeling of the many and conflicting biological properties determining the therapeutic utility of a drug candidate. Here we survey their suitability for key tasks involving the use of chemoinformatics methods in medicinal chemistry and drug discovery.

This article reviews multi-criteria QSAR applications on Acetylcholinesterase inhibitors as palliative drugs for Alzheimer's Disease, published in the period 2001-2011. It includes QSAR models for different series of compounds, comparative studies, and advances in methodologies. This period is marked by a shift in focus from palliative treatment to pathogenesis. However, we believe that research into palliative treatment should continue. More comparative studies are desirable. In order to facilitate comparative and general studies on Acetylcholinesterase inhibitors, a standard experimental protocol for measuring an inhibitor's potency is needed. Finally, we recommend chemists to work closely with system and molecular biologists.

With the significant increase of life expectancy of populations in societies today, the importance of the discovery of drugs associated with neurodegenerative diseases has emerged. Therefore, neurodegenerative diseases are an important topic in Medicinal Chemistry. Although drug discovery is considered a complex and slow process, new approaches and methods have been developed with the intention of finding new chemical entities in more efficient ways. This work provides a review of virtual methodologies applied in drug discovery and especially a new model for the prediction of MAO-A inhibitors using a multi-target QSAR methodology. This model involves a mixed approach containing simple descriptors based on atom-centered fragments and functional groups (DRAGON) and topological substructural molecular design descriptors (MODESLAB). This unified multi-species QSAR model was validated through a virtual screening of a new series of oxoisoaporphine derivatives, taking into account the information in the calculated fragmental contributions. Therefore, this method represents a useful tool for the in silico screening of MAO-A inhibitors.

CNS drug development is characterized by an especially high attrition rate, despite clear unmet medical needs in the field of neuro-pharmacology and significant investment in R&D of novel CNS drug treatments. Here, we overview the issues underlying the intrinsic difficulty of CNS drugs development, including obstacles of pharmacokinetic nature and lack of predictivity of preclinical tests. We highlight current efforts to overcome these limitations, with an emphasis on modeling opportunities towards early recognition of CNS candidates (stressing the possibilities of multi-target directed ligands or “magic shotguns”) and different approaches to improve CNS bioavailability.

The matrix protein 2 of the influenza A virus (M2 or AM2) is one of the important components of the viral membrane. This protein can form a proton channel in the viral envelope. Owing to its ability to regulate the surrounding pH in endosome, this protein is an attractive target for drug design against influenza A virus. In this minireview, we summarized the current progresses in computational approaches for studying the M2 proton channel. The attention is focused on how protons are conducted through the M2 channel, and how adamantane-based drugs inhibit the channel, as well as how the drug resistance occurs, in hope to further stimulate the in-depth studies of this important area, both experimentally and theoretically.

De-novo drug design (DND) is a complex procedure, requiring the satisfaction of many pharmaceutically important objectives. Several computational methodologies employing various optimization approaches have been developed to search for satisfactory solutions to this multi-objective problem varying from composite methods, which transform the problem to a single objective one to Pareto methods searching for numerous solutions compromising the objectives. In this review we initially focus on the DND problem and the challenges it poses to computational methods, followed by an examination of the reported methodologies and specific applications. Emphasis is placed on the multiobjective nature of the problem, related considerations and the solutions proposed by the drug discovery community.

Cancer cells are able to elaborate enzymatic mechanisms allowing tumors to resist or escape imune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that initiates the first and rate-limiting step of tryptophan breakdown along the kynurenine pathway, has emerged as a promising molecular target for the development of new immunotherapeutic anticancer agents. This review summarizes the synthesis and IDO activities of the different classes of marine and other inhibitors reported so far.

Thrombophilias are defined as a predisposition to thrombosis due to hematological changes which induce blood hypercoagulability; they can be inherited or acquired. They are individually characterized by a large phenotypic variability, even when they occur within the same family. Hereditary thrombophilias are, in most cases, due to changes related to physiological coagulation inhibitors or mutations in the genes of coagulation factors. High levels of plasma homocysteine may also be responsible for vaso-occlusive episodes and may have acquired (nutritional deficiencies of folate and vitamins B6 and B12) and/or genetic causes (mutations in the genes responsible for expression of enzymes involved in the intracellular metabolism of homocysteine). Considering that: (1) thromboses are events of multigenic and multifactorial etiopathology; (2) the presence of mutations in several genes significantly increases the risk of their occurrence; (3) the vascular territory (venous and/or arterial) affected involves different pathophysiological mechanisms and treatments, knowledge of genetic variants that may contribute to the risk and variability of the phenotypic manifestations of these diseases is extremely important. This understanding may provide support for a more individualized and therefore more effective treatment for thrombophilia carriers. Thus, this mini-review aims to address a comprehensive summary of thrombophilias and thrombosis, and discuss the role of polymorphisms in Factor V (FV Leiden), Prothrombin, Plasminogen activator inhibitor type-1 (PAI-1), Methylenetetrahydrofolate reductase (MTHFR) and Cystathionine β-synthase (CBS) genes as risk factors for thrombophilias.

Drug development in the recent times often relies on use of natural and synthetic drugs that are promising candidates as therapeutic agents for prevention of diseases and disorders. They possess different chemical structures with wide range of therapeutic activities. Many natural and synthetic drugs act as antioxidant agents in various metabolic processes. Increasing epidemiological, clinical and experimental studies have shown that intake of antioxidants drugs provide protection against various disorders and diseases related to oxidative stress. The factors responsible for this oxidative stress are mainly free radicals, reactive nitrogen species (RNS) and reactive oxygen species (ROS). The antioxidant drugs act as free radical scavenging, reducing and metal chelating substances; Antioxidants also show inhibition of various metabolic enzymes and factors responsible for inflammation. The present paper reviews different In vitro assays for determination of antioxidant activities (Table 1). The basic assays include DDPH assay, OH Scavenging assay, Reducing activity assay, TEAC assay, FCR assay, PRTC assay, ABTS assay, FRAP assay, ORAC assay, Ferric thiocynate assay, TRAP assay, Chemiluminescence assay, NBT assay, CUPRAC Assay.

Epilepsy is a chronic disorder of abnormal electrical activity in the brain characterized by recurrent unprovoked seizures. Currently used pharmaceutical agents do not treat the underlying disease process, and a significant proportion of epileptic patients are refractory to current therapies. Therefore there is a strong need for additional therapeutic agents, especially those that address the underlying disease process of epileptogenesis. The redox potential of cells is maintained by an appropriate balance between pro- and anti-oxidative molecules; oxidative stress and increases in toxic reactive oxygen species occur when this balance shifts towards oxidation. Neural tissues are especially sensitive to oxygen levels, and oxidative stress is thought to be involved in epileptogenesis. Increases in reactive oxygen species occur in response to sustained neuronal electrical activity and seizures. Therefore antioxidants have been suggested as therapeutic design strategies for the treatment and modulation of epilepsy. This minireview focuses on several key antioxidants and agents involved in defending against oxidative stress that may be targets for new antiepileptogenic drug design, including directacting antioxidants, Nrf2-activating agents, and prolyl-4-hydroxylase inhibitors. A description of the necessary physicochemical properties and a summary of animal models that are thought to be useful for developing antiepileptogenic agents are presented.

Cytochrome P450 (CYP) inhibition and induction are the key mechanisms in drug-drug interactions which should be avoided in clinic for the uncertain influence on the efficacy and safety of drug co-administration. The CYPmediated drug-drug interactions urgently need to be predicted by in vitro models before animal and clinical trials, while the primary hepatocytes may represent the most appropriate experimental system by now. However, traditional twodimensional (2D) culture of hepatocyte monolayer, regardless of the good facilitation and repeatability, rapidly loses its CYP-inducibility during short-term culture due to the deviated microenvironments from in vivo. Also, 2D culture did not reproduce the CYP-inhibition mediated hepatotoxicity in drug co-administration. Recently, three-dimensional (3D) cultured hepatocytes have been recognized as the promising models for predicting in vivo drug-drug interactions. The 3D cultures such as sandwich and gel entrapped hepatocytes showed the comparable response to CYP inhibitors and inducers as in vivo and well reflected the inhibitor/inducer mediated hepatotoxicity. In this regard, this review, for the first time, compares the effect of 2D and 3D hepatocyte cultures on reflecting CYP-mediated drug-drug interactions in vivo. And the advantage of 3D cultured hepatocytes on predicting in vivo CYP-induction/inhibition will be particularly discussed.