Multitarget Activity Research Articles

New therapeutic strategies for IPF: Based on the “phagocytosis-secretion-immunization” network regulation mechanism of pulmonary macrophages

Pulmonary fibrosis is a chronic and progressive interstitial lung disease of known and unknown etiology. Over the past decades, macrophages have been recognized to play a significant role in IPF pathogenesis. According to their anatomical loci, macrophages can be divided to alveolar macrophages (AMs) subtypes and interstitial macrophages subtypes (IMs) with different responsibility in the damage defense response. Depending on diverse chemokines and cytokines in local microenvironments, macrophages can be induced and polarized to either classically activated (M1) or alternatively activated (M2) phenotypes in different stages of immunity. Therefore, we hypothesize that there is a “phagocytosis-secretion-immunization” network regulation of pulmonary macrophages related to a number of chemokines and cytokines. In this paper, we summarize and discuss the role of chemokines and cytokines involved in the “phagocytosis-secretion-immunization” network regulation mechanism of pulmonary macrophages, pointing toward novel therapeutic approaches based on the network target regulation in the field. Therapeutic strategies focused on modifying the chemokines, cytokines and the network are promising for the pharmacotherapy of IPF. Some Traditional Chinese medicines may have more superiorities in delaying the progression of pulmonary fibrosis for their multi-target activities of this network regulation.

Towards multi-target antidiabetic agents: Discovery of biphenyl-benzimidazole conjugates as AMPK activators.

Type 2 diabetes mellitus is a complex metabolic disorder requiring polypharmacology approaches for effective treatment. Combinatorial library of fifteen new tricyclic benzimidazole derivatives have been designed and synthesized to combine fragments commonly found in allosteric AMPK activators and AT1 receptor antagonists. It was found that 2'-cyanobiphenyl serves as the pharmacophore of AMPK-activating activity, which also increases with the expansion of the external hydrogenated cycle. Also, pronounced antiplatelet activity is characteristic of the studied compounds. One of derivatives was identified as a potent inhibitor of the formation of advanced protein glycation end-products with reactive dicarbonyl scavenging activity. Two submicromolar AMPK activators 2b and 3b prevents inflammatory activation of murine macrophages. Along with good water solubility and synthetic availability, these results render biphenyl derivatives of fused benzimidazoles as a valuable starting point for the development of AMPK activators with multi-target antidiabetic activity.

Network pharmacology study of traditional Chinese medicines for stroke treatment and effective constituents screening

Ethnopharmacological relevanceStroke is one of the most frequent causes of death and disability. So far there are no effective preventives or treatments. The therapeutic system of traditional Chinese medicines (TCMs) has been in use for several thousand years and still affords a valuable resource for today's clinicians in preserving health. Materials and methodsWe had collected the Chinese medicinal formulae and then commonly used single herbs or drug combinations were analyzed through data mining. The ingredients from the top 30 frequently used herbs which have good druggability and blood-brain barrier permeability were collected as a natural product library. Targets of the related ingredients were predicted using various databases and analyzed by GO and KEGG pathway mapping. The potential stroke targets were validated in the market or from clinical trials, and used to establish molecular docking, HipHop and SBP models to screen new compounds for multi-target activity. Lastly, in vitro experiments with models for oxygen and glucose deprivation and reperfusion (OGDR) were conducted to test the activities of compounds identified by screening. ResultsA total of 1679 Chinese medicinal formulas were selected and their prescription rules were analyzed. 4277 compounds were from the top 30 herbs and 3560 molecules were filtered to build the natural product library. The ingredient-target network, target-disease network and target-target interaction network were established to explain the characteristics and mechanisms of the TCMs. Thirty-one molecules were selected to have multi-target activity on targets of stroke via virtual screening. Five of these had already been reported to have therapeutic effects on stroke. Three of the eight compounds which have been examined showed protective effects on OGDR model. ConclusionsThis paper details a novel strategy for exploring the characteristics and mechanisms of herbal medicines from a systematic standpoint in an attempt to identify those affecting specific target pathways related to stroke. Using this methodology on our natural products library, we found a number of lead candidates with multi-target activity.

Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors

A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11–16) and (indazole-5-yl)methanimines (17–22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17–22 as the amide spacer in their carboxamide analogs 11–16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.

Extended Multitarget Pharmacology of Anticancer Drugs

Multitarget pharmacology of small-molecule cancer drugs significantly contributes to their mechanism of action, side effects, and emergence of drug resistance and opens ways to repurpose, combine, or customize drug therapy. In most cases, the set of targets affected at therapeutic concentrations is not fully characterized and/or the interaction efficacy values are not accurately quantified. We collected information about multiple targets for each cancer drug along with their experimental effective concentrations or binding activities from multiple sources. All multitarget activity values for each drug then were used to build two proximity network pharmacology maps of anticancer drugs and targets of those drugs, respectively. Together with the network map, we showed that the majority of the cancer drugs had substantial multitarget pharmacology based on our current knowledge. In addition, most of the cancer drugs simultaneously affect macromolecular targets from different classes and types. The target subset can further be accentuated and personalized by patient sample-specific expression data. The network maps of cancer drugs and targets as well as all quantified activity data were integrated into a freely available database, CancerDrugMap (http://ruben.ucsd.edu/dnet/maps/drugnet.html). The identified multitarget pharmacology of cancer drugs is essential for improving the efficacy of individually prescribed drugs and drug combinations and minimization of adverse effects.

Prediction of Different Classes of Promiscuous and Nonpromiscuous Compounds Using Machine Learning and Nearest Neighbor Analysis

The ability of compounds to interact with multiple targets is also referred to as promiscuity. Multitarget activity of pharmaceutically relevant compounds provides the foundation of polypharmacolog...

Systematic computational identification of promiscuity cliff pathways formed by inhibitors of the human kinome.

The ability of a small molecule to interact with multiple target proteins provides the molecular basis of polypharmacology. So-defined compound promiscuity is intensely investigated in drug discovery. For example, for kinase inhibitors, the interplay between target selectivity and promiscuity plays a decisive role for different therapeutic applications. The "promiscuity cliff" (PC) concept was introduced previously to aid in promiscuity analysis. A PC is defined as a pair of structurally similar compounds with a large difference in promiscuity. Accordingly, PCs can reveal small structural modifications that might be responsible for selectivity or multi-target activity. In network representations, PCs form clusters of varying size and complexity that are difficult to analyze interactively. Herein, we introduce a computational method to systematically identify PC pathways, which are particularly rich in structure-promiscuity information, and extract them from PC clusters. PC pathways provide informative templates for experimental design. In a proof-of-concept investigation, we have applied the new computational approach to systematically identify pathways in more than 600 PC clusters formed by inhibitors of the human kinome, demonstrating the utility of the method and revealing many interesting promiscuity patterns.

Cytotoxic Stilbenes and Derivatives as Promising Antimitotic Leads for Cancer Therapy

The growing incidence of cancer, the toxic side-effects associated with conventional chemotherapeutic agents and the development of multidrug resistance (MDR) drive the search for novel and more effective drugs with multi-target activity and selectivity towards cancer cells. Stilbenes are a group of naturally occurring phenolic compounds of plant origin derived from the phenylpropanoid pathway that may exist as cis- or trans-isomers. Although the trans-isomer is the more common and stable configuration, resveratrol being a representative compound, cis-stilbenes are potent cytotoxic agents that bind to and inhibit tubulin polymerization, destabilizing microtubules. This review summarizes the chemistry and biological evaluation of cytotoxic stilbenes and their synthetic derivatives as promising antimitotic leads for cancer therapy, focusing on the most potent compounds, the combretastatins. Combretastatins isolated from the South African bushwillow Combretum caffrum are among the most potent antimitotic and vascular disrupting agents (VDAs) of natural origin. Preclinical studies have demonstrated their potent antitumor effects in a wide variety of tumors, both in vitro and in vivo, being currently under evaluation in phase 2 and phase 3 clinical trials for several types of solid tumors. Topics covered herein include synthetic medicinal chemistry, modes of action, structure-activity relationships (SAR), preclinical and clinical studies as VDAs in cancer therapy, either as single agents or in combination with cytotoxic anticancer drugs, antiangiogenic agents, or radiation therapy, and development of appropriate formulations based on nanocarriers (e.g., liposomes, nanoemulsions, polymeric, lipid and ceramic nanoparticles, carbon nanotubes) for improved bioavailability and targeted delivery of combretastatins to the tumor vasculature.

Recent Progress in Structure-Based Evaluation of Compound Promiscuity

In chemistry and drug discovery, compound promiscuity is a controversial issue and often viewed differently. On the one hand, promiscuity has a clear-cut negative connotation, as promiscuous behavior of small molecules is often associated with nonspecific binding or assay artifacts. On the other hand, it is also well-established that compounds frequently interact with multiple targets including distantly related or unrelated proteins. In drug discovery, multitarget activity of small molecules receives increasing attention because it is therapeutically relevant, giving rise to desired or undesired pharmacological effects. Exploration of compound promiscuity is far from being simple because true and artificial activities are often difficult to discern. In light of these complications, X-ray structures of ligand–target complexes provide a wealth of information about molecular promiscuity, which is just beginning to be recognized and explored. Systematic analysis of structurally confirmed binding events invol...

Neurotherapeutic potential of kolaviron on neurotransmitter dysregulation, excitotoxicity, mitochondrial electron transport chain dysfunction and redox imbalance in 2-VO brain ischemia/reperfusion injury

This study investigated the effects of post-treatment with kolaviron on a 2-Vessel Occlusion (2-VO) model of cerebral ischemia/reperfusion (I/R) injury in rats to ascertain its level of efficacy as a potential therapeutic agent for stroke. Male Wistar rats submitted to 30 min of bilateral common carotid artery occlusion and 24 h of reperfusion were treated with kolaviron (25–100 mg/kg) or 20 mg/kg quercetin immediately after reperfusion and 2 h post reperfusion. At the end of the period of reperfusion, animals were scored for motor and cognitive deficits. Brain relative weight and water content were determined. Cortices, striata and hippocampi were dissected and processed for estimation of markers of oxidative stress, inflammation, neurotransmitter dysregulation and excitotoxicity. In addition, assessment of hippocampal mitochondrial integrity and histopathological examination of the cortical, striatal and hippocampal regions were carried out. There was reversal of 2-VO ischemia/reperfusion (I/R) induced motor and cognitive deficits by kolaviron post-treatment. Post-treatment with kolaviron also attenuated I/R-induced oxidative stress, neuroinflammatory events, excitotoxicity as well as mitochondrial dysfunction in brain tissues. Histopathological findings showed amelioration of I/R-induced neuronal cell damage by kolaviron post-treatment. The results revealed the multi-target neurotherapeutic activity of kolaviron and suggest that it is a promising candidate for drug development against stroke.

Small Multitarget Molecules Incorporating the Enone Moiety.

Chalcones represent a class of small drug/druglike molecules with different and multitarget biological activities. Small multi-target drugs have attracted considerable interest in the last decade due their advantages in the treatment of complex and multifactorial diseases, since “one drug-one target” therapies have failed in many cases to demonstrate clinical efficacy. In this context, we designed and synthesized potential new small multi-target agents with lipoxygenase (LOX), acetyl cholinesterase (AChE) and lipid peroxidation inhibitory activities, as well as antioxidant activity based on 2-/4- hydroxy-chalcones and the bis-etherified bis-chalcone skeleton. Furthermore, the synthesized molecules were evaluated for their cytotoxicity. Simple chalcone b4 presents significant inhibitory activity against the 15-human LOX with an IC50 value 9.5 µM, interesting anti-AChE activity, and anti-lipid peroxidation behavior. Bis-etherified chalcone c12 is the most potent inhibitor of AChE within the bis-etherified bis-chalcones followed by c11. Bis-chalcones c11 and c12 were found to combine anti-LOX, anti-AchE, and anti-lipid peroxidation activities. It seems that the anti-lipid peroxidation activity supports the anti-LOX activity for the significantly active bis-chalcones. Our circular dichroism (CD) study identified two structures capable of interfering with the aggregation process of Aβ. Compounds c2 and c4 display additional protective actions against Alzheimer’s disease (AD) and add to the pleiotropic profile of the chalcone derivatives. Predicted results indicate that the majority of the compounds with the exception of c11 (144 Å) can cross the Blood Brain Barrier (BBB) and act in CNS. The results led us to propose new leads and to conclude that the presence of a double enone group supports better biological activities.

Neural network modeling of multitarget RAGE inhibitory activity

Based on the methodology of artificial neural networks, models describing the dependence of the level of RAGE inhibitory activity on the affinity of compounds for target proteins of the RAGE-NF-kB signal pathway have been costructed. A validated database of the structures and activity levels of 183 known compounds, which were tested for RAGE inhibitory activity was formed. The analysis of the AGE-RAGE signaling pathways was carried out, 14 key RAGE-NF-kB signal pathway nodes were found, for which 34 relevant target proteins were identified. A database of 66 valid 3D models of 22 target proteins of the RAGE-NF-kB signal chain was compiled. Ensemble molecular docking of 3D models of 183 known RAGE inhibitors into sites of 66 valid 3D models of 22 relevant RAGE target proteins was performed and minimum docking energies for each compound were determined for each target. According to the method of artificial multilayer perceptron neural networks, classification models were constructed to predict level of RAGE inhibitory activity based on the calculated affinity of compounds for significant target proteins of the RAGE-NF-kB signaling chain. The prognostic ability of these models of RAGE-inhibitory activity was evaluated, the maximum accuracy according to ROC-analysis was 90% for a high level of activity. The sensitivity analysis of the developed multitarget models were carried out, the most significant targets of the RAGE-NF-kB signal transmission chain were determined. It was found that for high level of RAGE inhibitory activity, the most significant biotargets are not AGE receptors, but eight signaling kinases of the RAGE-NF-kB pathway and transcription factor NF-kB1. Thus, it is suggested that known compounds with high RAGE-inhibitory activity are preferential inhibitors of signal kinases.

Curcumol: From Plant Roots to Cancer Roots.

Natural products, an infinite treasure of bioactive scaffolds, have provided an excellent reservoir for the discovery of drugs since millennium. These naturally occurring, biologically active and therapeutically effective chemical entities have emerged as novel paradigm for the prevention of various diseases. This review aims to give an update on the sources as well as pharmacological profile of curcumol, a pharmacologically active sesquiterpenoid, which is an imperative bioactive constituent of several plants mainly from genus Curcuma. Curcumol has potential to fight against cancer, oxidative stress, neurodegeneration, microbial infections, and inflammation. Curcumol has been documented as potent inducer of apoptosis in numerous cancer cells via targeting key signaling pathways as MAPK/ERK, PI3K/Akt and NF-κB which are generally deregulated in several cancers. The reported data reveals multitarget activity of curcumol in cancer treatment suggesting its importance as anticancer drug in future. It is speculated that curcumol may provide an excellent opportunity for the cure of cancer but further investigations on mechanism of its action and preclinical trials are still mandatory to further validate the potential of this natural cancer killer in anticancer therapies.

Standardized Xin-Ke-Shu tablets improves the disturbances of lipid, energy, and amino acid metabolism in a rabbit model of atherosclerosis

Objective: Xin-Ke-Shu (XKS), a patent drug, used to treat coronary artery diseases in China for many years. Previous research indicates that XKS has similar therapeutic effect as atorvastatin (AS) against atherosclerotic in rabbits. However, biochemical assays demonstrate that XKS could have a different therapeutic mechanism from AS. The aim of this study is to explore the mechanism of XKS therapeutic effect, especially those different from AS. Materials and Methods:1H nuclear magnetic resonance-based metabonomics were applied to profile the low-molecular-weight polar metabolites in the plasma of rabbits fed a high cholesterol diet. Results: Seven of the eleven pathological biomarkers related to atherosclerosis in rabbits were mediated by XKS treatment, namely low-density lipoprotein/very-low-density lipoprotein (LDL/VLDL), lactate, citrate, phosphatidylcholine, glutamine, creatinine, and methionine, as well as two characteristic metabolites of pyruvate and α-glucose. These metabolites involved lipid, energy, and amino acid metabolism, and all could be considered XKS treatment targets. However, AS only affected the metabolic disorders associated with LDL/VLDL and phosphatidylcholine, which is mainly target lipid metabolism. Conclusions: This study indicates that the anti-atherosclerosis effects of AS mainly involve reducing blood–lipid levels, but those of XKS involve a multitargeted activity.

The Multitarget Activity of Natural Extracts on Cancer: Synergy and Xenohormesis.

It is estimated that over 60% of the approved drugs and new drug developments for cancer and infectious diseases are from natural origin. The use of natural compounds as a potential source of antitumor agents has been deeply studied in many cancer models, both in vitro and in vivo. Most of the Western medicine studies are based on the use of highly selective pure compounds with strong specificity for their targets such as colchicine or taxol. Nevertheless, approximately 60% of fairly specific drugs in their initial research fail because of toxicity or ineffectiveness in late-stage preclinical studies. Moreover, cancer is a multifaceted disease that in most cases deserves a polypharmacological therapeutic approach. Complex plant-derived mixtures such as natural extracts are difficult to characterize and hardly exhibit high pharmacological potency. However, in some cases, these may provide an advantage due to their multitargeted mode of action and potential synergistic behavior. The polypharmacology approach appears to be a plausible explanation for the multigargeted mechanism of complex natural extracts on different proteins within the same signalling pathway and in several biochemical pathways at once. This review focuses on the different aspects of natural extracts in the context of anticancer activity drug development, with special attention to synergy studies and xenohormesis.

Computational Analysis of Kinase Inhibitors Identifies Promiscuity Cliffs across the Human Kinome

Kinase inhibitors are high-priority drug candidates for a variety of therapeutic applications. Accordingly, there has been a rapid growth in the number of kinase inhibitors and volumes of associated activity data. A paradigm for the use of kinase inhibitors in oncology is that these compounds have multitarget activities and elicit their therapeutic effects through polypharmacology. An analysis of kinase inhibitors and associated activity data from medicinal chemistry has so far only identified small subsets of highly promiscuous kinase inhibitors. In this study, we have collected inhibitors of human kinases and their activity data from seven public repositories, curated, and combined these data, yielding more than 112 000 inhibitors with well-defined activity measurements from which qualitative target annotations were derived. An analysis of these unprecedentedly large data sets revealed that nearly 40% of human kinase inhibitors have multikinase activities but that only 4% are known to be active against ...

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives.

Alkaloids, a category of natural products with ring structures and nitrogen atoms, include most U.S. Food and Drug Administration approved plant derived anti-cancer agents. Evodiamine is an alkaloid with attractive multitargeting antiproliferative activity. Its high content in the natural source ensures its adequate supply on the market and guarantees further medicinal study. To the best of our knowledge, there is no systematic review about the antiproliferative effects of evodiamine derivatives. Therefore, in this article the review of the antiproliferative activities of evodiamine will be updated. More importantly, the antiproliferative activities of structurally modified new analogues of evodiamine will be summarized for the first time.

CMAUP: a database of collective molecular activities of useful plants.

The beneficial effects of functionally useful plants (e.g. medicinal and food plants) arise from the multi-target activities of multiple ingredients of these plants. The knowledge of the collective molecular activities of these plants facilitates mechanistic studies and expanded applications. A number of databases provide information about the effects and targets of various plants and ingredients. More comprehensive information is needed for broader classes of plants and for the landscapes of individual plant’s multiple targets, collective activities and regulated biological pathways, processes and diseases. We therefore developed a new database, Collective Molecular Activities of Useful Plants (CMAUP), to provide the collective landscapes of multiple targets (ChEMBL target classes) and activity levels (in 2D target-ingredient heatmap), and regulated gene ontologies (GO categories), biological pathways (KEGG categories) and diseases (ICD blocks) for 5645 plants (2567 medicinal, 170 food, 1567 edible, 3 agricultural and 119 garden plants) collected from or traditionally used in 153 countries and regions. These landscapes were derived from 47 645 plant ingredients active against 646 targets in 234 KEGG pathways associated with 2473 gene ontologies and 656 diseases. CMAUP (http://bidd2.nus.edu.sg/CMAUP/) is freely accessible and searchable by keywords, plant usage classes, species families, targets, KEGG pathways, gene ontologies, diseases (ICD code) and geographical locations.

Origanum vulgare essential oils inhibit glutamate and aspartate metabolism altering the photorespiratory pathway in Arabidopsis thaliana seedlings

Essential oils (EOs) have been extensively studied as valuable eco-friendly compounds with herbicidal activity for weed management. Phytotoxic potential of EOs, extracted from a wild population of Origanum vulgare ssp. hirtum (Link) Ietswaart, has been here evaluated on plant model Arabidopsis, through a physiological and metabolomic approach. The EOs composition was mainly characterized by monoterpenes and sesquiterpenes, with a strong abundance of two monoterpenic phenols, namely carvacrol and thymol, and the monoterpene o-cymene. The in vitro bioassay confirmed a strong phytotoxic effect of EOs on Arabidopsis rosettes, showing by both a strong growth reduction and highly chlorotic leaves. In well-developed seedlings, EOs firstly caused growth reduction and leaf chlorosis, together with a series of interconnected metabolic alterations: i) impairing the nitrogen assimilation into amino acids, which affects in particular the glutamine metabolism; and as consequence ii) excessive accumulation of toxic ammonia into the leaves, associated with oxidative stress and damage; iii) declining the efficiency of the photosynthetic apparatus, connected to the reduced CO2 fixation and photooxidation protection; iv) impairing the photorespiratory pathway. Overall, the results highlights that EOs alters principally the ability of Arabidopsis seedlings to incorporate inorganic nitrogen into amino acids, principally glutamine, leading to a dramatic accumulation of ammonia in leaf cells. This primary effect induces, in turn, a cascade of reactions that limits the efficiency of PSII, inducing oxidative stress and finally causing a strong plant growth reduction, leaf necrosis and eventually plant death.These findings suggest that O. vulgare EOs might be proficiently exploited as a potential bioherbicide in an ecofriendly agriculture. Moreover, its multitarget activity could be advantageous in limiting weed resistance phenomenon.

Differential Potentiation of Retinoic Acid Effects against Human Breast Cancer Cells by Unsaturated Fatty Acids

Retinoic acid (RA) and unsaturated fatty acids (UFA) are proposed as nutritional anticancer agents. Nonetheless, the activity of their combination on human breast cancer needs further study. Our aim was to evaluate this activity on the MCF-7 and ZR-75-1 cell lines treated with 1 µM RA and 50 µM of γ-linoleic (GLA, ω-6), eicosapentaenoic (EPA, ω-3), oleic (OA, ω-9), or eicosatrienoic (ETA, ω-9) acids. The following cellular responses were compared by ANOVA and Fisher test (P < 0.05): fatty acids, E-cadherin, actin (differentiation), conjugated dienes, γ-glutamyltranspeptidase activity (stress), and viability, which were correlated by partial least squares regression. Although both cell lines responded differentially, RA modified unsaturated fatty acids, increased differentiation, reduced γ-glutamyltranspeptidase, and viability. RA differentiating activity on ZR-75-1 was morphologically enhanced by UFA. Stress induction with γ-glutamyltranspeptidase decrease and conjugated dienes was promoted by ETA in MCF-7, and EPA and OA in ZR-75-1. RA-related reduced viability was potentiated by EPA and OA in both lines. GLA was less active. Therefore, unsaturated fatty acids (ω-3/ω-9) potentiated the multitarget retinoic acid activity against these human breast cancer cells.