Current Enzyme Inhibition (v.12, #1)

Meet Our Editorial Board Member: by Sibel Süzen (1-1).

Nitric Oxide Synthases and Their Natural Inhibitors by Christos Kontogiorgis, Dimitra Hadjipavlou-Litina (3-15).
Nitric Oxide (NO) is a molecule of extreme interest to biologists, pharmacologists, physiologists, and biochemists, characterized as a mediator in the cardiovascular system. It has been found to be implicated in various pathological processes. NO is synthesized enzymatically by Nitric Oxide Synthases (NOSs) from L-arginine, and therefore NOSs have emerged as very crucial therapeutic targets. Herein, a series of extracts from plants as well as a number of isolated compounds acting as NOS inhibitors are presented.

NO (Nitric oxide) is a signaling molecule and exhibits a plethora of biological activities. Three isoforms of NOS (Nitric Oxide Synthase) are involved in NO production viz. iNOS, eNOS and nNOS. Evidence from research shows that pathological conditions such as arthritis, asthma, cardiovascular dysfunctions, hypertension, neurodegeneration and septic shock arise due to an imperfect control of the NO levels.
NOS inhibitors have emerged as the successful solution for control of NO levels. Most of the research attention and expenditure are focused on the two isoforms, iNOS, and nNOS, due to their involvement in various pathological conditions. Due to its physiological role, eNOS is excluded as a drug target. Despite innumerable NOS inhibitors available, selectivity towards a particular isoform, poses a serious challenge in the design of successful inhibitors. With the help of advancement in the respective fields of synthesis, modeling software, bioassays, molecular biology and the perception of the far reached functions of NO and role of NOS enzyme; successful efforts have been made by various groups of scientists to get more selective, potent and less toxic inhibitors. The present review summarizes in and out of the various approaches used in the designing of non-selective and selective inhibitors in the recent past.

Recent Developments of Amidine-like Compounds as Selective NOS Inhibitors by Nazzareno Re, Marialuigia Fantacuzzi, Cristina Maccallini, Roberto Paciotti, Rosa Amoroso (30-39).
The first generation of Nitric Oxide Synthases inhibitors was synthesized in the late 1980's and early 1990's; they were mainly amino acid derivatives, binding to the same residues within the enzyme heme-active site with respect to the natural substrate L-Arg, and showed no or scarce selectivity. In 1994, the N-(3-(aminomethyl)-benzyl) acetamidine (1400W), a highly selective compound for human iNOS versus both human eNOS and nNOS, was discovered. Following this landmark discover several other amidine-based iNOS and nNOS selective inhibitors have been disclosed. In this review we will focus on the recent progress and perspectives in the development of amidine-based selective iNOS and nNOS, including close analogues, with particular attention to acetamidine and aminopyridine derivatives.

Nitric oxide is being explored for the treatment of neuropsychiatric disorders since decades. The molecule has shown to alter different neurotransmitters comprising norepinephrine, serotonin, glutamate and dopamine and thus plays an important role in the neurobiology of major depression. A large number of studies have depicted a dual-nature of this molecule in the pathophysiology of major depression and related neuropsychiatric disorders. It is well known that an enzyme responsible for the production of nitric oxide in the body viz. Nitric Oxide Synthase (NOS) is expressed in different areas of the brain. Interestingly, multiple antidepressants have shown to alter the levels of nitric oxide in the body, as demonstrated through animal studies. When determined using human subjects, patients suffering from major depression have altered levels of nitric oxide. With this background, we presented here a review gathering different studies describing the role of this small molecule in the neurobiology of major depression. Some of the studies conducted in our laboratory, exploring the role of L-arginine-nitric oxide-cyclic guanosine monophosphate signaling pathway in the effect of various conventional and novel antidepressants, have been listed here. It is our hypothesis that nitric oxide modulating antidepressants may be the future line of treatment in patients suffering from major depression, especially in cases of pharmacoresistant depression.

Nitric Oxide Synthase (NOS) Inhibitors in Cancer Angiogenesis by Amit K. Halder, Avinaba Mukherjee, Nilanjan Adhikari, Achintya Saha, Tarun Jha (49-66).
Nitric Oxide (NO) is the smallest known molecule in the mammalian biological signaling system. It is well established in the field of molecular biology as an endothelium derived growth factor. It is biosynthesized from L-arginine by three enzyme isoforms - endothelial NOS (eNOS or NOS3), neuronal NOS (nNOS or NOS1) and inducible NOS (iNOS or NOS2). In last two decades, all these enzyme isoforms were investigated to understand their roles in different pathological conditions. The relation between these enzymes and cancer is ambiguous and complex as NOS enzymes have been found to be both pro- and anti-tumorigenic. Although the exact functions of NOS enzymes in cancer progression is still under investigation, some recent reports repeatedly highlighted roles of iNOS and eNOS enzymes in the development of angiogenesis in cancer. As per the latest reports, eNOS should be the most important NOS isoform involved in angiogenesis. The current review highlights the aspect and latest developments of NOS inhibitors as anti-angiogenic agents in cancer. In addition, we report molecular modeling analyses (2D and 3D QSAR, pharmacophore modeling and molecular docking) of some reported eNOS inhibitors to understand structural requirements of these molecules for higher activity.

Quantitative Structure-Activity Relationship Studies on Nitric Oxide Synthase Inhibitors by Satya P. Gupta, Harish Kumar, Basheerulla Shaik (67-80).
It has been observed that the overproduction of Nitric Oxide (NO) causes disfunction of several organs and affects lactate level. Hence, attempts have been made to design and develop potent inhibitors for Nitric Oxide Synthases (NOSs), the enzymes which are responsible for its production. NOSs exist mainly in three different isoforms: neuronal, inducible, and endothelial, designated as nNOS, iNOS, and eNOS, respectively. For design and development of potent NOS inhibitors against all the 3 isoforms several Quantitative Structure-Activity Relationship (QSAR) studies were made. This article compiles comprehensively all such studies and discusses critically their outcome. For the inhibitors of all isoforms, some pharmacophore models have been developed in which commonly at least one H-bond donor, one H-bond acceptor, one hydrophobic group, and in some positively charged moieties have been found to be essential. Consistent to these pharmacophores, 2D and 3D QSAR studies have pointed out that all NOS inhibitors undergo H-bond, hydrophobic, electronic and steric interactions with the receptors.

Inhibitors of Nitric Oxide Synthase: What's up and What's Next? by Lakshmikirupa Sundaresan, Suvendu Giri, Suvro Chatterjee (81-107).
NO is a key signaling molecule that has a wide range of biological functions including vasodilation and neurotransmission, and is implicated in several pathological conditions. Therefore, modulation of NO is a desired step in curbing the NO-associated disease processes. Targetting NOS proteins and inhibiting their activity to reduce NO production is a major approach since the inception of NOS inhibitor research. Although a series of NOS inhibitors have been developed, synthesized and practiced in experimental biology, no NOS inhibitor has been approved as yet a drug for therapeutic uses. The present review elaborates the scope of the clinical uses of NOS inhibitors and the inherent limitations of the process that makes the approach less successful so far in clinic.