Current Medicinal Chemistry (v.20, #13)
Editorial (Hot Topic: Complexity against Complexity: Multitarget Drugs) by Diego Munoz-Torrero (1621-1622).
Human Disease and Drug Pharmacology, Complex as Real Life by E. Viayna, I. Sola, O. Di Pietro, D. Munoz-Torrero (1623-1634).
In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypicscreening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusivelyand potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target toavoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approachhas been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy andsafety. In this context, a network biology perspective of human disease and treatment has burst into the drug discoveryscenario to bring it back to the consideration of the complexity of living organisms and particularly of the(patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoringaction. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore,not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnectedmanner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailingsingle-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexityof human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuseargument that is spurring the development of multitarget therapies.
The Economics of Polypharmacology: Fixed Dose Combinations and Drug Cocktails by A. I. Wertheimer (1635-1638).
The history of Fixed Dose Combination (FDC) oral drug products has been tumultuous over its history. SomeFDCs were prepared for marketing purposes and others for clinical improvements. Often, the products prepared for marketingadvantage ended up causing negative outcomes. However, in recent years, there has been a resurgence of FDCs asclinicians have found them adventitious for treatment of AIDS/HIV and for oral contraceptives, just to name two examples.International regulatory Agencies and most major drug regulatory agencies have established guidelines along withregulations concerning preparation, labeling and marketing for FDCs. The advantages of FDCs are said to be in the clinicalrealm where simplified therapy regimens are thought to enhance patient
Polypharmacology in a Single Drug: Multitarget Drugs by M. L. Bolognesi (1639-1645).
Polypharmacology offers a model for the way drug discovery must evolve to develop therapies most suited totreating currently incurable diseases. It is driven by a worldwide demand for safer, more effective, and affordable medicinesagainst the most complex diseases, and by the failures of modern drug discovery to provide these. Polypharmacologycan involve combinations and/or multitarget drugs (MTD). Although not mutually exclusive, my premise is thatMTDs have inherent advantages over combinations. This review article focuses on MTDs from a medicinal chemistryperspective. I will explore their use in current clinical practice, their likely application in the future, and the challenges tobe overcome to achieve this goal.
Predicting Targeted Polypharmacology for Drug Repositioning and Multi- Target Drug Discovery by X. Liu, F. Zhu, X. H. Ma, Z. Shi, S. Y. Yang, Y. Q. Wei, Y. Z. Chen (1646-1661).
Prediction of polypharmacology of known drugs and new molecules against selected multiple targets is highlyuseful for finding new therapeutic applications of existing drugs (drug repositioning) and for discovering multi-targetdrugs with improved therapeutic efficacies by collective regulations of primary therapeutic targets, compensatory signallingand drug resistance mechanisms. In this review, we describe recent progresses in exploration of in-silico methods forpredicting polypharmacology of known drugs and new molecules by means of structure-based (molecular docking, binding-site structural similarity, receptor-based pharmacophore searching), expression-based (expression profile/signaturesimilarity disease-drug and drug-drug networks), ligand-based (similarity searching, side-effect similarity, QSAR, machinelearning), and fragment-based approaches that have shown promising potential in facilitating drug repositioning andthe discovery of multi-target drugs.
Rationally Designed Multi-Targeted Agents Against Neurodegenerative Diseases by W. J. Geldenhuys, C. J. Van der Schyf (1662-1672).
Neurodegenerative diseases are complex disorders with several pathoetiological pathways leading to cell death.Rationally designed multi-targeted agents, or
Multi-Target Compounds Acting in the Central Nervous System Designed From Natural Products by X. Chen, M. Decker (1673-1685).
Modern medicinal chemistry has come to its bottleneck and is full of challenges, specially when facing withlong-term central nervous system (CNS) disorders induced by several factors, such as Alzheimer
Multitarget Drugs of Plants Origin Acting on Alzheimer's Disease by P. Russo, A. Frustaci, A. Del Bufalo, M. Fini, A. Cesario (1686-1693).
The etiopathology of Alzheimer
Rationally Designed Multitarget Anticancer Agents by Zhuo Chen, Le Han, Minghao Xu, Yufang Xu, Xuhong Qian (1694-1714).
Balanced modulation of multiple targets is an attractive therapeutic strategy in treating complex diseases includingcancer. Comparing with drugs combination, single molecule modulating desirable multiple targets has advantagesin pharmacokinetic and pharmacodynamics. Different from previous reviews, we provided an overview of reported multitargetantitumor agents from the viewpoint of pharmacophores. These multitarget antitumor agents were designed bycombination of pharmacophores or by high-throughput screening plus structural modification, which were exemplified bythe privileged pharmacophore quinazoline and several other popular pharmacophores, including phenylaminopyrimidine,anthracycline and naphthalimide. Previous research demonstrated the importance of in-depth validation against multipletargets not only in cell-free system, but also in cancer cells. Furthermore, the multitarget compounds were also effectivefor resistance cell lines which highlighted their antitumor potency in the era of increasing drug resistance in cancer patients.
Recent Developments in Rationally Designed Multitarget Antiprotozoan Agents by P. M. Njogu, K. Chibale (1715-1742).
Protozoan infections are the leading cause of morbidity and mortality among parasitic infections of humans,accounting for approximately 800 thousand mortalities and a loss of more than 30 million disability-adjusted life yearsannually. The major protozoan infections of humans, namely malaria, Chagas disease, human African trypanosomiasis,and leishmaniasis, are primarily centered in the tropics, with a reach into some subtropical regions of the world. Thoughglobally massive in their impact, these diseases mostly afflict the least economically endowed and geographically marginalizedpopulations in low-income countries. As such, there is no sufficient market incentive for industrial businessdrivenantiprotozoal drug discovery due to poor marketing prospects and low returns on investment. Consequently, thepharmacopoeia for majority of these diseases, composed mainly of agents with poor efficacy and unsatisfactory safetyprofiles, has essentially remained unchanged for decades, creating a compelling need for more efficacious and better toleratedmedicines. The policy makers and the scientific community are seeking effective ways to meet this need. So far,two approaches have emerged promising in this regard: combination chemotherapy and drug repositioning. Molecular hybridizationhas been cited as a potential third approach that could be used to deliver new antiprotozoal chemical entities.In this review article, recent applications of this novel strategy in antimalarial, antichagasic, antitrypanosomal, and antileishmanialdrug discovery research and development over the last five years will be presented and discussed.
Rationally Designed Multitarget Anti-HIV Agents by P. Zhan, X. Liu (1743-1758).
Multitarget-directed ligands (MTDLs), an emerging and appealing drug discovery strategy, utilizing a singlechemical entity to inhibit multitargets, was confirmed to be effective in reducing the likelihood of drug resistance, diminishingproblems of dosing complexity, drug-drug interactions and toxicities, as well as improving patient compliance. Theexploration of MTDL strategy should be valuable in anti-HIV drug discovery. In this article, current knowledge andstrategies for the rational design of the multitarget and selective anti-HIV agents are described and a number of illustrativeexamples are given. Moreover, the challenges, limitations and outlook of such novel drug design strategies are also presented,with a goal to highlight the representative paradigms in the rational design of MTDLs, and to help medicinalchemists discover the next generation of multitarget anti-HIV agents.
Design of Multifunctional Compounds for Cardiovascular Disease: From Natural Scaffolds to by A. Bisi, S. Gobbi, F. Belluti, A. Rampa (1759-1782).
Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated bloodpressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required.Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis ofmultitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factorsinvolved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature onmultifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, consideringthat compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bearthe so-called
Rationally Designed Multitarget Agents Against Inflammation and Pain by S. H. Hwang, A. T. Wecksler, K. Wagner, B. D. Hammock (1783-1799).
Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of anumber of biologically active metabolites. For over a century, these biochemical transformations have been the target ofnumerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs(NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammationand pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findingsdemonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting asingle ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways inARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacyor reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the threepathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), andsummarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammationand pain.