Molecular Docking: Shifting Paradigms in Drug Discovery

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(18), P. 4331 - 4331

Published: Sept. 4, 2019

Molecular docking is an established in silico structure-based method widely used drug discovery. Docking enables the identification of novel compounds therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing priori chemical structure other target modulators. Although it was originally developed to help understanding mechanisms recognition between small and large molecules, uses applications discovery have heavily changed over last years. In this review, we describe how firstly applied assist tasks. Then, illustrate newer emergent docking, including prediction adverse effects, polypharmacology, repurposing, fishing profiling, discussing also future further potential technique when combined with techniques, such as artificial intelligence.

Language: Английский

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Toward Multi-Targeted Platinum and Ruthenium Drugs—A New Paradigm in Cancer Drug Treatment Regimens?

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(2), P. 1058 - 1137

Published: Jan. 14, 2019

While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination that we began to truly understand nature of bond and structures stereochemistries metal complexes. We can now readily manipulate fine-tune their properties. This had led a multitude complexes with wide-ranging biomedical applications. review will focus use potential as important therapeutic agents treatment cancer. With major advances in technologies deeper understanding human genome, are strong position more fully carcinogenesis at molecular level. also rationally design develop drug molecules either selectively enhance or disrupt key biological processes and, doing so, optimize potential. heralded new era which moving from single- toward multitargeted approach. approach lies very heart chemistry. In this review, have endeavored showcase how "multitargeted" families metallodrugs may only reduce systemic toxicities associated modern day chemotherapeutics but address resistance issues plaguing many chemotherapeutic regimens. focused our attention incorporating platinum ruthenium ions given containing these already clinical advanced trials anticancer agents. The described herein target DNA contain vectors enable them cancer cells and/or moieties enzymes, peptides, intracellular proteins. Multitargeted designed mitochondria inspired by natural product activity described. A summary field past decade so be provided.

Language: Английский

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Cholinesterase inhibitors as Alzheimer's therapeutics (Review)

Molecular Medicine Reports, Journal Year: 2019, Volume and Issue: unknown

Published: June 11, 2019

Alzheimer's disease (AD) is one of the most common forms dementia. AD a chronic syndrome central nervous system that causes decline in cognitive function and language ability. Cholinergic deficiency associated with AD, various cholinesterase inhibitors have been developed for treatment including naturally‑derived inhibitors, synthetic analogues hybrids. Currently, available drugs are predominantly inhibitors. However, efficacy these limited as they may cause adverse side effects not able to completely arrest progression disease. Since multifactorial disease, dual multi‑target developed. The clinical applications limitations used treat discussed present review. Additionally, this review presents current status future directions development novel reduced toxicity preserved pharmacological activity.

Language: Английский

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Marine Natural Products: A Source of Novel Anticancer Drugs

Marine Drugs, Journal Year: 2019, Volume and Issue: 17(9), P. 491 - 491

Published: Aug. 23, 2019

Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes action and thus considerable research has been conducted anticancer from natural sources, especially plants, microbes marine organisms. Marine populations represent reservoirs bioactive metabolites diverse groups chemical structures. This review highlights impact organisms, particular emphasis on algae, bacteria, actinomycetes, fungi, sponges soft corals. Anti-cancer effects products in vitro vivo studies were first introduced; their activity prevention tumor formation related compound-induced apoptosis cytotoxicities tackled. The possible molecular mechanisms behind biological are also presented. diversity structures, property space. Finally, therapeutic strategies present use marine-derived components, its future direction limitations discussed.

Language: Английский

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Recent Developments on Therapeutic and Diagnostic Approaches for COVID-19

The AAPS Journal, Journal Year: 2021, Volume and Issue: 23(1)

Published: Jan. 1, 2021

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) has made a serious public health threat worldwide with millions people at risk in growing number countries. Though there are no clinically approved antiviral drugs and vaccines for COVID-19, attempts clinical trials several known drugs, their combination, as well development patients confirmed COVID-19. This review focuses on latest approaches to diagnostics therapy We have summarized recent progress conventional therapeutics such vaccines, anti-SARS-CoV-2 antibody treatments, convalescent plasma which currently under extensive research treatment developments nanoparticle-based therapeutic diagnostic been also discussed assessed literature data this topic summary current future perspectives.

Language: Английский

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Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 62(2), P. 420 - 444

Published: July 23, 2018

Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or metabolic syndrome. Polypharmacological profiles can produce additive synergistic effects while reducing side and significantly contribute high therapeutic success indispensable drugs aspirin. While their identification has long been result serendipity, medicinal chemistry now tends design polypharmacology. Modern vitro pharmacological methods chemical probes allow systematic search for rational combinations recent innovations computational technologies, crystallography, fragment-based equip multitarget compound development with valuable tools. In this Perspective, we analyze multiple ligands versatile toolbox We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential secure future innovation.

Language: Английский

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Molecular Hybridization as a Tool for Designing Multitarget Drug Candidates for Complex Diseases

Current Topics in Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 19(19), P. 1694 - 1711

Published: June 26, 2019

Molecular hybridization is a well-exploited medicinal chemistry strategy that aims to combine two molecules (or parts of them) in new, single chemical entity. Recently, it has been recognized as an effective approach design ligands able modulate multiple targets interest. Hybrid compounds can be obtained by linking (presence linker) or framework integration (merging fusing) strategies. Although very promising combat the multifactorial nature complex diseases, development molecular hybrids faces critical issues selecting right target combination and achievement balanced activity towards them, while maintaining drug-like-properties. In this review, we present recent case histories from our own research group demonstrate why how carried out address challenges multitarget drug discovery therapeutic areas are Alzheimer's parasitic diseases. Selected examples spanning linker- fragment- based will allow discuss consequences relevant design.

Language: Английский

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Rational Design of Multitarget-Directed Ligands: Strategies and Emerging Paradigms

Journal of Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 62(20), P. 8881 - 8914

Published: May 13, 2019

Due to the complexity of multifactorial diseases, single-target drugs do not always exhibit satisfactory efficacy. Recently, increasing evidence indicates that simultaneous modulation multiple targets may improve both therapeutic safety and efficacy, compared with drugs. However, few multitarget are on market or in clinical trials, despite best efforts medicinal chemists. This article discusses systematic establishment target combination, lead generation, optimization multitarget-directed ligands (MTDLs). Moreover, we analyze some MTDLs research cases for several complex diseases recent years physicochemical properties 117 drugs, aim reveal trends insights potential use MTDLs.

Language: Английский

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Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy

Nature Materials, Journal Year: 2019, Volume and Issue: 18(12), P. 1376 - 1383

Published: Oct. 21, 2019

Language: Английский

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Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders

Pharmacology & Therapeutics, Journal Year: 2019, Volume and Issue: 204, P. 107402 - 107402

Published: Aug. 27, 2019

Current medication for anxiety disorders is suboptimal in terms of efficiency and tolerability, highlighting the need improved drug treatments. In this review an overview drugs being studied different phases clinical trials their potential treatment fear-, anxiety- trauma-related presented. One strategy followed development refining improving compounds interacting with existing anxiolytic targets, such as serotonergic prototypical GABAergic benzodiazepines. A more innovative approach involves search novel mechanisms action using growing knowledge base concerning relevant neurocircuitries neurobiological underlying pathological fear anxiety. The target systems evaluated include glutamate, endocannabinoid neuropeptide systems, well ion channels targets derived from phytochemicals. Examples promising candidates currently generalised disorder, social panic obsessive compulsive disorder or post-traumatic stress ketamine, riluzole, xenon one common pharmacological modulation glutamatergic neurotransmission, neurosteroid aloradine. Finally, D-cycloserine, MDMA, L-DOPA cannabinoids have shown efficacy enhancing fear-extinction learning humans. They are thus investigated augmentative speeding up long-term effectiveness exposure-based psychotherapy, which could render chronic dispensable many patients. These efforts indicative a rekindled interest renewed optimism discovery field, after decades relative stagnation.

Language: Английский

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