Frontiers in Computational Chemistry: Volume 4 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Computational Chemistry
- Sprache: Englisch
Frontiers in Computational Chemistry presents contemporary research on molecular modeling techniques used in drug discovery and the drug development process: computer aided molecular design, drug discovery and development, lead generation, lead optimization, database management, computer and molecular graphics, and the development of new computational methods or efficient algorithms for the simulation of chemical phenomena including analyses of biological activity. The fourth volume of this series features four chapters covering natural lead compounds, computer aided drug discovery methods in Parkinson’s Disease therapy, studies of aminoacyl tRNA synthetase inhibition in bacteria, computational modeling of halogen bonds in biological systems and molecular classification of caffeine and its metabolites.
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Veröffentlichungsjahr: 2018
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PREFACE
Computational chemistry has grown to a large field that entails the use of computers to study a very broad range of chemical problems, and includes both the development (often referred to as “theoretical chemistry”) and applications. This broad range of computational approaches includes electronic structure calculations, molecules dynamics simulations, and free energy relationships (e.g., QSAR, QSPR). The focus of Frontiers in Computational Chemistry, is on the application of computational chemistry approaches to biological processes. While the overview of chapters included in this volume described below provides exciting specific studies, general topics covered in this series include computer aided molecular design, drug discovery and development, lead generation, lead optimization, database management, computer and molecular graphics, and the development of new computational methods or efficient algorithms for the simulation of chemical phenomena, including the analyses of biological activity.
In this fourth volume, five chapters that present a diverse spectrum of approaches towards biological processes are presented including:
Chapter 1 “Natural Lead Compounds and Strategies for Their Optimization as New Drugs” provides strategies to improve possible lead compounds for use in medicine. Dev Bukhsh Singh describes how a combination of approaches including high-throughput screening, structure activity relationships, absorption, distribution, metabolisms, excretion, and toxicity (ADMET) parameters can be used to optimize lead compounds.
Chapter 2 “Computer-aided Drug Discovery Methodologies in the Modeling of Dual Target Ligands as Potential Parkinson’s Disease Therapeutics” by Yunierkis Perez-Castillo and co-authors, presents advances in the application of drug discovery methodologies in modeling dual target ligands for the discovery of potential Parkinson’s Disease therapeutics. A virtual screening method was developed to aid in the prioritization of potential dual binder candidates.
Chapter 3 “Molecular Studies of the Inhibition of Aminoacyl tRNA Synthetases in Microbial Pathogens”. In this chapter, Nilashis Nandi describes progress made towards molecular-level insight into the inhibition of aminoacyl tRNA synthetases (aaRSs), which are promising targets for the development of new inhibitors. Insight is gained using a number of methods including structural analysis based on crystallographic and NMR measurements, as well as mutation studies, kinetic methods, and molecular dynamics simulations.
Chapter 4 “Advances in the Computational Modelling of Halogen Bonds in Biomolecular Systems: Implications for Drug Design”. P.J. Costa and Rafael Nunes provide an overview of computational methods to model halogen bond interactions in biomolecular systems such as protein-ligand complexes is provided. The practicality of the approaches in computer-aided drug design and discovery is discussed.
Chapter 5 “Molecular Classification of Caffeine, Its Metabolites, and Nicotine Metabolite” by Francisco Torrns and Gloria Catellano show the use of structure-property relationships to model retention times for caffeine and caffeine and nicotine metabolites.
We hope that the readers will find these reviews valuable and thought provoking so that they may trigger further research in the field. We are grateful for the timely efforts made by the editorial personnel, especially Ms. Mariam Mehdi (Assistant Manager Publications), Mr. Shehzad Naqvi (Editorial Manager Publications), and Mr. Mahmood Alam (Director Publications) at Bentham Science Publishers.
This volume is dedicated to Jeffry D. Madura who was a professor at Duquesne University (USA) and an editor of the first three volumes of this series. We thank Jeff not only for his role as an editor of the prior volumes in this series, but, also acknowledge his scientific contributions. He passed away too early and the chemistry community will miss him.
List of Contributors
Natural Lead Compounds and Strategies for Optimization
Dev Bukhsh Singh*Abstract
Natural lead is a chemical compound derived from living organism. Nature provides a vast set of structurally diverse compounds that can be used as a medicine. Traditional knowledge of natural medicine will remain as an important source of future medicine and therapeutics. A lead compound in drug discovery possesses some therapeutic applicability, but it may require a series of structural changes to serve as a drug. The chemical structure of the lead molecule is used as a starting point for chemical modifications in order to improve its selectivity, potency, pharmacodynamics and pharmacokinetic parameters. The high-throughput screening (HTS) techniques are used to screen thousands of compounds to identify potential drug candidates for a given drug target. The structure-activity relationship (SAR) and absorption, distribution, metabolisms, excretion and toxicity (ADMET) parameters and other related drug-likeness properties of a lead can be optimized to discover a potential drug. ADMET assays measure and define the properties such as the rate of metabolism, non-specific and plasma-protein binding, permeability, liver and kidney toxicity, LogP and solubility. Furthermore, the process of lead optimization improves the poor drug-likeness of the lead and a new candidate drug can be recommended for in vitro or clinical testing.
INTRODUCTION
According to the World Health Organization (WHO), health is a state of complete physical, mental and social well-being, not merely the absence of disease or infirmity [1]. A disease may be defined as a particular abnormal condition which adversely affects a part or all of the organism. Drugs have the capability to restore imbalance or disequilibrium leading to the cure of disease. There are different categories of diseases based on metabolism, immune system, inheritance,
pregnancy, injury, infection and environmentally acquired disorders. A drug is a chemical substance required for the treatment, cure, diagnosis or prevention of disease or to promote good health status. There are different types of drugs-depending on their nature and response. Nature is one of the major sources of medicinal agents for thousands of years [2]. This chapter describes the role of natural compounds in drug discovery process, with a focus on lead discovery and lead optimization strategies. Plant-based traditional medicine system (80% population) plays a very important and essential role in health care. A number of phytochemicals are present in the plants which act as cell modifiers in the human system. One or more parts of the medicinal plants contain different compounds that can be used for the therapeutic purpose [3]. A majority of drugs have been developed from natural plant metabolite or derived from the compounds from natural sources. There are many plant-derived substances such as curcumin, piperin and many others, for which a number of drug targets are available in the human body.
United Nations Convention on Biological Diversity confirms the rights of source nations over their genetic materials and also promotes the protection of local and indigenous knowledge, practices, and innovations. The medicinal roles of phytochemicals from many plants have been reported, and are in use as a medicine against many diseases [4]. These phytochemicals are phenolics, polyphenols, quinones, flavones, flavonols, flavonoids, coumarins, terpenoids and oils, alkaloids, lectins and polypeptides, glycosides and others. Phytochemicals stimulate the physiological activities of the human system and generate a wide range of pharmacological response. Phytochemicals form a complex with target proteins through forces such as hydrogen bonding, hydrophobic interaction and covalent bonding, and produce a pharmacological response [5]. Inhibition or activation of a drug target or modulation of a disease related pathway results in a therapeutic effect in a diseased state. There are many plants which have great potential for the treatment of many diseases but they have not been explored and well documented yet. Natural products and their derivatives are the main sources of structural diversity for the drug discovery process [6]. A natural product is a chemical compound produced by living organism in nature that has some biological activity. It can be extracted from the tissues of plants, animals, marine organism or microbes. Natural products can be extracted as such or can be synthesized. Synthesis of many natural products is difficult and is expensive to produce them at a large scale. Most of the clinically used therapeutics is being produced by in vitro chemical synthesis. It is difficult to synthesise structurally complex metabolites such as taxol and vincristine by in vitro synthesis [7].
Therapeutic efficacy of the leads can be optimized to achieve a high pharmacological response on treatment. Lead compounds should have good potency and specificity for a drug target so that they can be transformed into an active drug after lead optimization. Lead optimization improves the specificity and selectivity of a chemical compound for drug target, pharmacodynamics and to develop a potential drug candidate.
KEY STAGES IN DRUG DISCOVERY PROCESS
Drug discovery programme is necessary to find the therapeutic solution for a disease. Drug discovery process includes identification and validation of drug target, assay development, lead identification and optimization, screening and identification of potential drug candidate, clinical trial, and feedback, and approval of drug and marketing (Fig. 1). A drug fails if it does not generate therapeutics response or has a toxic effect on human. Target identification and validation is the most important step in the development of a drug. It enables us to predict the response of a drug and explore the mechanism-based side effects. A broad class of biological entities such as proteins, nucleic acids, carbohydrates, and lipids can serve as drug targets. Gene or gene products also interact with drugs. Drugs should be designed keeping in mind the proteins, enzymes or receptors related to ADMET properties to achieve the maximum therapeutic benefits. Druggable genome defines the set of genes that encode promising drug targets. Identification of druggable genes in various diseases can help the process of drug development. Genome-wide association studies (GWAS) help in identification of druggable targets and its interaction with the drugs.
Fig. (1)) Key steps in modern drug development process.A potential drug target needs to be safe, efficacious, specific and druggable. Biomedical data mining using bioinformatics approaches helps in identification, selection, and validation of potential disease targets. Differential expression of an mRNA or protein in normal and diseased condition also enables us to identify a drug target. A drug target can be validated through multiple approaches to increase the confidence level [8]. Antisense technology is a powerful approach which involves binding of an antisense molecule to target mRNA and prevents the related protein synthesis. In contrast to gene knock out approach, the effect of an antisense approach is reversible. Monoclonal antibodies are also used for target validation as they interact with the large region of the target protein. Chemical genomics is the study of genomic response to a chemical compound [9]. This approach is also very useful in identification and validation of a drug target.
Compound screening assays for a disease are developed during hit identification and lead discovery process of drug designing. Hit is a compound which shows the desired activity in screen but it needs to be tested further. Exploitation of drug-like compound databases and database of target genes and proteins facilitates the designing of new chemical entities through molecular modeling approach [10]. High throughput screening has the capability to screen the entire library of compounds against a target in a complex assay system. Knowledge-based screening selects a small subset of compounds from a library that may have activity against a target protein based on scientific and literature knowledge. Cell-based assays have been applied to membrane receptors, ion channels, and nuclear receptors to assess the activity of compounds [11]. Biochemical assays are applied to both receptors and enzyme targets which measure the affinity of a compound with the target protein. A plethora of assays is available and the choice of assay formats mainly depends upon the nature of drug target. During an assay selection, the pharmacological relevance of assay, reproducibility, quality, cost and effect of a compound in the assay should be considered as important points [12].
Once a number of hits have been obtained, then it becomes very important and decisive to define which compound is best to work on. Drug discovery tools are used to cluster entire hits based on structural similarity and representative molecules are selected from a diverse set of compounds for further optimization. Drug discovery process should be initiated with a small molecule as lead optimization may increase molecular weight. Traditional medicine system promotes the plant-based drug discovery process through investigation of leads from natural sources [13]. The main objective of lead optimization is to develop more potent and selective compounds which possess desired pharmacokinetic activity in vivo model. Structure-based drug designing techniques can be applied to find the information of binding site on target protein.
Molecular docking techniques are employed to find the top scoring compounds that have a high binding affinity for the binding site of target protein [14]. Computational chemistry tools speed up the process of drug discovery by playing a very significant role in modeling, designing, searching of analogues, pharma- cophore mapping, pharmacophore based searching, virtual screening, molecular dynamics simulation, pharmacokinetics and pharmacodynamics studies. Eval- uation of absorption, distribution, metabolism, and toxicity (ADMET) parameters are very important for a compound to qualify as a drug. Once candidate drugs are determined, they are subjected to different stages of the clinical trial to ensure its efficacy and non-toxic response in the human. A drug needs to be approved by drug administration authority before its large-scale synthesis and release into the market. Advances in the synthetic chemistry enable the chemical synthesis of many elucidated structures [15]. Major side effects of a drug are monitored and reviewed from time to time and its license can be revoked if major adverse effects are reported in the human population. Drugs derived from natural sources have a low chance of failure due to side effects. There are a series of hurdles for a compound must pass to qualify as a drug.
Ligand-based drug designing is based on the interaction between the ligand and target binding site. The structural details of ligand-protein interaction are determined from the crystalline enzyme-inhibitor complex. Binding site and the binding interactions between protein-ligand is determined through computational tools [16]. The cavity in the binding site of receptor-ligand interaction can be located, and a substituent of appropriate size can be created on ligand to fill in the cavity to achieve the extra binding stability. A number of computational tools are available for prediction of cavities or pockets on protein surface where ligand can bind. There may be a number of cavities in a protein but in most of the cases cavity with largest area and volume is associated with the binding site. The accuracy of binding site prediction should be high enough to proceed for molecular docking and virtual screening. Grid-based, sphere-based, α-shape-based and probe energy-based methods are available for cavity or pocket prediction. A large number of analogues or similar compounds are designed and docking approaches are used to find the fitness and binding capacity of these compounds into binding site. In de novo designing, the structural detail of binding between ligand and enzyme is determined by x-ray crystallography [17]. Potential binding regions in the binding site of the enzyme is identified by removing the ligand. A lead compound is searched, designed and synthesized to test the selectivity and activity for the target enzyme. The complex of a lead compound with the target enzyme is crystallized to find the actual binding information. After this step, a structure-based drug designing is applied.
ROUTE OF A DRUG AND ITS FATE
Absorption of drug depends on the ionization of drug and surface area of stomach and intestine. The surface area of the intestine is much larger and permeable than stomach, thus it provides fast and efficient drug absorption. The stomach (low pH) favors the high undissociated concentration of acidic drug compared to high pH of the intestine [18]. Weakly acidic drugs are more readily absorbed by an acidic environment than weakly basic drugs. Oral absorption of drug depends on physicochemical and biopharmaceutical properties of the drug [19]. It is expected that orally active drug should satisfy the Lipinski rule of five to achieve high biological activity. This rule describes the pharmacokinetics (ADME) of a drug, therefore, Lipinski parameters should keep in mind during lead optimization. Route of a drug and its fate in the human body has been represented in the Fig. (2). Drug solubility, dissolution, and permeability across the route are the key factors controlling the drug absorption. Intestinal absorption of drugs in human can be predicted by theoretical computation of 2D molecular descriptors related to physicochemical properties such as lipophilicity, polarity, polarizability, and hydrogen bonding [20]. Hydrogen bonding properties have the largest impact on drug absorption and should be kept to a minimum to achieve high absorption. Low uptake of the drug in human increases the risk of side effects and toxicity. Oral bioavailability is one of the properties that need to be optimized. Absorption of a compound can be enhanced by changing the physicochemical properties of lead through lead optimization.
Fig. (2)) Route of a drug and its fate in the human body after oral administration.After absorption, a drug enters in the systemic circulation for its distribution to tissues of the body. Drug distribution is the process of delivering a drug molecule from the blood circulatory system to tissues of body and especially to the site of action [21]. Distribution of a drug depends on its lipophilicity, molecular size, degree of ionization, protein binding and affinity to other molecules. The greater the lipophilicity, the more is the distribution and vice versa. Smaller size drugs are more rapidly distributed than larger size drugs. The degree of ionization also affects the drug distribution because drugs can be trapped in a specific compartment when exists in ionized forms [22]. Different blood-brain barriers are present in the route of distribution which significantly decreases the degree of distribution. Endothelial cells, pericytes, and glial cells form the barriers in the passage of drug. Plasma proteins such as albumin, globulins, glycoproteins and lipoproteins bind with specific drugs [23]. Albumin is the most abundant plasma protein and it binds to acidic drugs. Drug distribution is described by the apparent volume of distribution which measures the relative distribution of a drug between tissue and plasma [24]. A drug should be selective to the target; otherwise, it will recognize off-targets in the body which may lead to toxicity.
Drug metabolism is the process of breakdown of drugs into active substances. Liver is the primary site of drug metabolism. Liver plays a major role in metabolism, digestion, detoxification, and elimination of chemical substances. The family of liver isoenzymes known as cytochrome P-450 (CYP) converts the drug into other metabolites. These metabolites bind with other substances for excretion through the lungs, saliva, sweat, urine or breast milk or may be reabsorbed in the intestine [25]. There are about 30 CYP enzymes, out of which CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are the major metabolizing enzymes [26]. CYP3A4 are the most important and clinically important enzymes in human. They metabolize nearly 50% of the drugs [27]. Knowledge of metabolic pathway, metabolite stability, toxicity and enzymes involved in drug metabolism is an important information in the process of drug development.
The rate of metabolism affects the oral bioavailability and elimination of drug in human. Structural modification of drug candidate can alter the drug metabolism. Highly lipophilic or highly hydrophilic drugs are not suitable because of poor bioavailability and poor excretion. Prior information on drug metabolism can guide the researcher to introduce a functional group which will alter metabolic stability as per requirement [28]. Replacing an active group with a non-reactive group can increase the metabolic stability. For example, replacing a methyl group with a t-butyl group can prevent demethylation.
LEAD DISCOVERY
In lead discovery, active new chemical entities are determined, which by lead optimization may be transformed into a clinically useful drug. Lead compounds should have desired potency and selectivity for the target. Synthesis of a lead compound should be easy and is should be amenable to chemical modification. Its formulation should not be problematic. The drug should be easily converted into the pill, gel, cream suitable for treatment condition. It should be free from structural elements that provoke toxicity; for example, alkylating agents and Michael acceptors [29]. A lead compound can be identified through the following routes: 1) By chance observations of a compound in study (Example: Penicillin) 2) optimizing the side effects of a compounds 3) Knowledge from herbal / folk remedies 4) Screening of product metabolites from natural sources 5) High throughput screening of compound libraries 6) Rational drug design 7) Natural substrate-based drug design. It requires a lot of effort to transform a lead compound into a drug candidate.
A lead compound with inappropriate distribution parameters can be improved by the process of lead optimization. Physicochemical and biochemical properties such as solubility, permeability, and metabolic stability determine the pharmacokinetics of a drug [30]. Physicochemical and biochemical properties of a compound are very useful in guiding the structural changes required to improve drug-likeness. Attention should be paid on optimizing those properties which allow the discovery of a candidate that possess all the qualities of a successful drug. Approximately 39% drugs fail in the development process because of poor bioavailability and pharmacokinetic properties.
Natural Lead
There are many known drugs that cause a little or more side effects in human. The folk or herbal remedies serve as useful starting points for the identification of lead compounds. It is exciting that 80% of the world’s population uses the drugs derived from natural sources [31]. Another interesting fact is that about 35% of drugs have key structural elements of natural origin. There is a broad scope of natural lead compounds because only 5% of the 500,000 higher plant species have been studied for their pharmacology [32]. Each plant contains potentially 10,000 different constituents.
The active components and pharmacological response of the rest of the herbal plants can be explored to achieve the goal of drug discovery. Each plant has potentially many thousand different constituents. Many drugs are derived from natural products and that natural compounds have served as excellent lead compounds. Natural compound screening is a widely used method to find lead compounds. Plant and animal extracts, marine organisms, microbial products are used in biological assays to find some biological activity [33]. For this purpose, a target is identified and a bioassay is developed. In case of a positive hit, the active constituent is isolated from the herbal extract to serve as a lead compound. One of the advantages of natural product screening is that nature provides a vast set of structurally diverse compounds. In drug discovery process, more priority is given to the lead compounds derived from natural sources. List of some natural leads their sources and therapeutic applications have been listed in the Table 1 [7, 34]. 2D structure of some natural lead compounds are shown in Fig. (3).
Fig. (3)) 2D structure of some natural lead compounds.There are some problems associated with natural products screening. The herbal extracts are often very complex and contain many diverse and large macromolecules such as carbohydrates, lipids, and proteins [35]. It is very problematic to isolate an active component of herbal mixture present in a very small amount. Isolation and structure determination of a compound is also a difficult and laborious task. Sometimes synthesis of the compound becomes challenging [36]. Identification of pharmacophore is also a complex task. A pharmacophore is the key structural element of a compound required for its biological activity.
Therapeutic Role of Some Natural Leads
Curcumin
Curcumin is a secondary metabolite of turmeric, derived from Curcuma longa L. Curcumin has a plethora of targets and has many biological activities. Several curcumin derivatives have been synthesized and their mechanisms of action related to different pharmacological responses have been discovered [37]. Curcumin has been reported to possess antitumor, antiviral, antibacterial, antifungal, anti-inflammatory, antioxidant, neuroprotective, anti-aging and other therapeutic properties [38, 39]. Curcumin inhibits the arachidonic acid metabolism, lipoxygenase, cyclooxygenase, cytokines, Nuclear factor-kB and release of steroidal hormones. Curcumin stabilizes the lysosomal membrane and causes uncoupling of oxidative phosphorylation which is responsible for its anti-inflammatory response [40]. Curcumin has shown binding to numerous inflammatory molecules (tumor necrosis factor α, cyclooxygenase, α1-acid glycoprotein and myeloid differentiation protein 2), cell survival proteins, histone acetyltransferase, histone deacetylase, glyoxalase I, xanthine oxidase, proteasome, HIV1 integrase, HIV1 protease, sarco (endo) plasmic reticulum Ca2+ ATPase, DNA methyltransferases 1, DNA polymerase λ, Ribonuclease A, lipoxygenase, matrix metalloproteinases, lysozyme, protein kinases (protein kinase C, viral sarcoma, gylycogen synthase, kinase-3β, ErbB2 and phosphorylase kinase), protein reductases (thioredoxin reductase and aldose reductase), carrier proteins (casein, albumin, fibrinogen, β-lactoglobulin and immunoglobulin), FtsZ protofilaments, transthyretin, tubulin, aminopeptidase N, β-amyloid aggregates, glutathione, prion protein, DNA, RNA and metal ions [41].
Piperin
Black pepper (Piper nigrum) is most commonly used spice in human diets for several thousands of years [42]. It is also used as a medicine, preservative, and perfume. Piperine is an active phenolic component of black pepper. It stimulates the digestive enzymes of the pancreas, lowers lipid peroxidation, acts as an antioxidant, and enhances the bioavailability of therapeutic drugs [43]. Another natural compound gaultherin, a salicylate derivative extracted from Gaultheria yunnanensis, has also been reported to have analgesic and anti-inflammatory effects and lack gastric ulcerogenic effect compared to aspirin [44]. The anti-inflammatory activities of piperin have been demonstrated in rat models. Studies have shown the in vitro inhibitory activity of piperin against the enzymes responsible for leukotriene and prostaglandin biosynthesis, 5-lipoxygenase and COX-1, respectively [45]. Piperin can be beneficial for the treatment of inflammatory diseases such as rheumatoid arthritis. Rheumatoid arthritis is characterized by inflammatory immune cell infiltration into the synovial fluid and cartilage destruction. Thus, piperine should be further studied with regard to its anti-inflammatory role and its activity can be optimized to find a drug for the treatment of arthritis and other inflammatory diseases.
Inflammatory bowel disease (IBD) causes chronic inflammation of the intestinal tract. Baicalin and artemisinin have been used as therapeutics for the treatment of IBD. Studies have shown that pre-administration of piperine decreases clinical hallmarks of colitis in DSS treated pregnane X receptor (PXR) mice [46]. The level of inflammatory mediators (CCR2, IL-1β, ICAM-1, IL-6, IL-10, MCP-1, iNOS, and TNFα) was significantly reduced in mice pre-treated with piperine. Piperine has been reported as a potential agonist of PXR, which may induce CYP3A4 gene expression at the mRNA and protein levels.
Piperine has been reported to have an anti-cancer activity for the variety of cancer cell lines. Injection of piperine (2.5 and 5 mg/kg) suppress the primary 4T1 tumor growth and injection of piperine (5 mg/kg) significantly inhibits the lung metastasis [47]. Recently, anti-tumor mechanisms of piperine have been investigated on androgen dependent and androgen independent prostate cancer cells. Piperine causes activation of caspase-3 and cleavage of PARP-1 proteins in LNCaP, PC-3 and DU-145 prostate cancer cells [48]. Piperine reduces the level of androgen receptor and prostate specific antigen in LNCaP prostate cancer cells. These results support the further investigation of piperine as a potential therapeutic agent for the treatment of prostate cancer. The anticancer and cancer preventive activity of a piperine-free P. nigrum extract was studied against breast cancer cells and N-nitrosomethylurea (NMU)-induced tumorigenesis in rats [49]. The results of this study indicate PFPE as a potent antitumor agent with a low toxicity.
The different mechanism for the bioavailability of piperin has been proposed such as modulation of signal transduction and inhibition of drug-efflux. Piperin is known to inhibit drug metabolizing enzymes, stimulate absorption, and inhibit the cell pump responsible for drug efflux [50]. Piperine inhibits human P-glycoprotein and cytochrome P450 3A4 (CYP3A4) which is associated with the first-pass elimination of many drugs [51]. It also inhibits or induces some drug metabolizing enzymes such as CYP1A1, CYP1B1, CYP1B2, CYP2E1, and CYP3A4.
Artemisinin
Artemisinin is obtained from an aromatic annual herb Artemisia annua L. Artemisinin-based antimalarial has contributed significantly to reduce the malaria deaths [52]. The mechanism of action of artemisinin is still controversial. Enzyme ATP6 of Plasmodium falciparum has been proposed as a target of action for artemisinin. Proteins related to glycolysis, hemoglobin digestion pathway, DNA synthesis, protein synthesis and lipid synthesis has also been proposed as a target for artemisinin [53]. Now, the aim is to find a functionally most important target for an antimalarial response. Artemisinin and curcumin have potential to kill Plasmodium falciparum in culture. Artemisinin inhibits the growth of ring forms of Plasmodium falciparum in human and also reduces their abundance [54]. The efficacy of artemisinin was found far superior to quinine and chloroquine. The poor drug properties and low bioavailability of artemisinin restrict its clinical application. Artemisinin-related drugs can be developed by utilizing the lead optimization strategies.
Charantin
It is natural steroidal glycoside present in the fruit juice of Momordica charantia. Fruit juice of this plant possesses potential hypoglycaemic activity and has been used for the treatment of diabetes for centuries [55]. The extract of this plant contains two biologically active components including glycosides (charantin and momordin) and alkaloids (momordicin). This plant has also been used for the treatment of many antiviral, antibacterial and pathogenic diseases. There is need to evaluate the pharmacological response of this compound clinically.
Ribosome-inactivating proteins (RIPs) from plants have brought attention in biomedical research because they target host protein synthesis machinery. RIPs are members of the single chain ribosome inactivating protein (SCRIP) family which inhibits the protein synthesis by removing purine residue from eukaryotic r RNA [56]. RIPs have been reported in Momordica charantia. MAP30 (Momordica Anti-HIV Protein) and momorcharins inhibit HIV replication in infected cells [57]. MAP30 possess important therapeutic role against HSV and HIV infection and is also nontoxic to normal cells.
Teniposide
Podophyllotoxin is isolated from dried root and rhizome of Podophyllum peltatum [58]. Teniposide has been developed from the Podophyllotoxin. Glioma is a type of tumor that develops from glial cells in the brain or spine. MicroRNAs play important roles in tumor progression and drug resistance. MiR-181b has been reported as a positive regulator of glioma cell sensitivity to teniposide [59]. It confers sensitivity to teniposide through binding to the 3’-UTR of MDM2 leading to its reduced expression.
Topoisomerases are ubiquitous enzymes that are essential for DNA super coiling, replication and transcription. Inhibitors of topoisomerases are commonly used as anti-cancer and antibacterial agents [60]. Topoisomerase inhibitors specifically bind at the interface of topoisomerase-DNA complex. Teniposide, etoposide, and other podophyllotoxin analogues cause transient DNA breaks by targeting the DNA. These agents inhibit the catalytic activity of topoisomerase II and, also stabilize the covalent intermediate formed between the DNA and the enzyme [61]. Topoisomerase II inhibitors are highly selective to target cancer cells. Teniposide is not more potent than etoposide, but it is more readily taken up by cells than etoposide cells which may result in greater cytotoxicity.
Colchicine
Colchicine is a natural product originally extracted from plants of the genus Colchicum (autumn crocus) [62]. Gout is an inflammatory arthritis which occurs because of precipitation of serum urate into deposits of monosodium urate crystals in the joint. Colchicine has the capability to modulate anti-inflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts activation of the inflammasome, microtubule-based chemotaxis, generation of leukotrienes and cytokines, and phagocytosis [63]. Colchicine can be used for the treatment of other inflammatory diseases that invoke these molecular pathways. Colchicine is an alkaloid that is also used for the treatment of familial Mediterranean fever. Molecular basis of colchicine action was analysed by its effect on global gene expression of human umbilical vein endothelial cell line [64]. Colchicine changes the expression of many genes known to be involved in the cell cycle and its regulation. The anti-inflammatory effect of colchicine is not only because of direct interaction with microtubules but also through changes at gene expression level.
Microtubules are an ideal target for anticancer drugs because they play an essential role in the formation of dynamic spindle apparatus. As such, there is a wide variety of compounds currently in clinical use and in development that act as antimitotic agents by altering microtubule dynamics. Taxane, vinca alkaloid, and colchicine are known to affect microtubule dynamics upon binding to microtubules [65]. Microtubule is an important therapeutic target in tumour cells. Drugs that bind to microtubules can be the only alternative to DNA as a therapeutic target for the treatment of cancer. Many anti-tubulin agents have been screened from botanical species and marine organism [66]. There is a need to develop novel anti-tubulin agents with enhanced specificity for tumours and reduced neurotoxicity.
Reserpine
Reserpine is derived from the root of tropical plant Rauwolfia serpentina [67]. It is used to treat snakebites, insomnia, and hypertension. The use of reserpine has been restricted because of its sedative response. The pharmacological response of reserpine methiodide (an analogue of reserpine) has been compared with reserpine for its central (barbiturate hypnosis, body temperature, and avoidance of conditioned response) and peripheral actions (blood pressure) [68]. Both reserpine and reserpine methiodide produce a dose-dependent reduction in the blood pressure. Reserpine methiodide does not produce any behavioural changes even at a higher dose.
Reserpine is a competitive inhibitor of both primary and secondary active transporter systems. Bacterial multidrug efflux pump is associated with the mechanism of bacterial resistance to antimicrobials. Reserpine has been reported to interact with multidrug efflux transporter (bmr) and inhibits the drug transport [69]. Reserpine does not completely inhibit the binding site of multidrug efflux pumps and its inhibition depends on the type of substrate [70]. Reserpine and other modulators of multidrug efflux pump can be useful in order to restore the clinical efficacy of chemotherapeutic agents against infectious diseases.
Strychnine
Strychnine is derived from the dried seed of plant nux vomica. The main bioactive constituents of nux vomica are alkaloids, responsible for both pharmacological and toxic response [71]. Strychnine and brucine constitute more than 50% of the total 16 alkaloids. The toxic response of nux vomica has limited its clinical applicability as a medicinal. Strychnine is a potent antagonist of glycine receptors in the central nervous system and a strong inhibitor of muscle and neuronal nicotinic acetylcholine receptors [72]. Strychnine possesses a little antitumor, analgesic and anti-inflammatory activity.
Codeine
Codeine is derived from dried milky exudates of unripe seed capsule of Papaver somniferum. In peripheral inflamed tissue opioid peptides are produced and released from immune cells and activate opioid receptors [73]. Codeine binds to opioid receptors located on neuronal cell membranes. Codeine is a prodrug with no analgesic effect. It must first be metabolized in the liver to its active metabolite, morphine [74]. Due to genetic variability in its hepatic conversion, individuals who are poor metabolizers of codeine will have less analgesic benefit.
Theobromine
Theobromine and caffeine are present in the beans of Theobroma cocoa. Theobromine is found in a higher amount than caffeine. Theobromine is useful in asthma and in other respiratory diseases such as a cough. Theobromine binds with poly(ADP-ribose)polymerase-1 and reduces inflammation of lungs caused by gamma-carrageenan [75]. Theobromine and caffeine are able to bind with ATP, DNA, and RNA. Theobromine is responsible for increasing the level of high-density lipid by inhibition of adenosine receptor [76]. Theobromine has the ability to improve the cognitive function and β-amyloid level in Alzheimer's disease model of rat [77]. Theobromine and its derivatives are used for the treatment of cardiac, lung and circulatory disorders, nephrotoxicity, proteinuria and also act as an immune-modulator. Recently, theobromine has been reported to increase the osteogenic potential of bone marrow osteoprogenitors [78].
Atropine
Atropine is an alkaloid extracted from the root of Atropa beladona [79]. It is an anticholinergic. Atropine blocks the acetylcholine receptor in the nervous system, stomach, intestines, salivary gland and urinary tract. It is used in traditional treatments for the headache, menstrual symptoms, inflammation, histaminic reaction, peptic ulcer and motion sickness [80]. It is also used for Parkinson's disease, a pain killer for joint pain and nerve pains. Atropine has the capability to increases the heart rate and improves the atrioventricular conduction by blocking the parasympathetic influences on the heart [81].
Vinblastine
Vinblastine is isolated from the Catharanthus roseus. It is a potent inhibitor of cell division that acts by disrupting spindle formation [82]. Vinblastine binds at the interface of two tubulin molecules and thus interferes with tubulin assembly [83]. Vinblastine is a chemotherapeutic agent against several types of cancers including Hodgkin’s and non-Hodgkin’s lymphoma, acute lymphocytic leukemia, breast and testicular cancer [84].
Taxol/Paclitaxel
Taxol is derived from the bark of Taxus brevifolia. It is used for the treatment of ovarian, breast, prostate, and lung cancer, as well as Kaposi's sarcom [85]. Paclitaxel treatment arrests mitosis, in both animal tumor models and cell culture. The binding of Taxol to β-tubulin in the polymer results in stabilizes the microtubules and reduces their dynamicity [86].
Rotenone
Rotenone is derived from the roots of certain plants, is a specific and potent inhibitor of mitochondrial NADH dehydrogenase (complex I) [87]. Reactive oxygen species (ROS) play an important role in apoptosis. Inhibition of mitochondrial respiratory chain complex I by rotenone elevates the mitochondrial ROS production [88]. Rotenone can induce apoptosis via enhancing the production of mitochondrial ROS. Rotenones possess anticancer activity through the induction of apoptosis in cancer cells. Rotenone induces apoptosis in human lung cancer cells by increasing NOX2-dependent ROS generation and autophagy [89]. Rotenone has shown a strong inhibitory effect against human breast cancer cells (MCF-7). It may induce apoptosis through activation of ROS and c-jun n-terminal kinase (JNK)/p-38 mitogen-activated protein kinase in MCF-7 cells [90]. Rotenone can be used to potentially target lung cancer, breast cancer and other types of cancer cells.
Salicin
Salicin is β-glycoside that contains D-glucose. It is extracted from the bark of Salix alba and possesses an anti-inflammatory role [91]. Salicin generates its pharmacological response by modulating the inflammatory process and inhibition of activation of activation of NF-kB, and subsequent down regulating COX-2 expression [92]. The discovery of aspirin, the most common anti-inflammatory drug is based on the structure of salicin. Bark extract of Salix alba has been found to possess anti-proliferative and pro-apoptotic effect in vitro study [93]. There is need to explore the anticancer potential and mechanism of action of salicin against cancer.
Digoxin
Digoxin/digitoxin is derived from the leaves of plant Digitalis purpurea. It contains four important glucosides (digitoxin digitalin digitalein and digitonin) of which three are cardiac stimulants [94]. All glycosides have a common pharmacophore of an aglycone ring structure. Digoxin inhibits the membrane-bound alpha subunits of sodium-potassium ATPase. Inhibition of sodium pump promotes sodium-calcium exchange and increases the concentration of intracellular calcium for contractile proteins, which increases the force of contraction of heart muscle [95
