Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies.

HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer's disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a "predictor" model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent ligands targeting AChE/MAO-A/MAO-B and also D1-R/D2-R/5-HT2A -R/H3-R are promising novel drug candidates with improved efficacy and beneficial neuroleptic and procognitive activities in treatment of Alzheimer's and related neurodegenerative diseases. Structural information for drug targets permits docking and virtual screening and exploration of the molecular determinants of binding, hence facilitating the design of multi-targeted drugs. The crystal structures and models of enzymes of the monoaminergic and cholinergic systems have been used to investigate the structural origins of target selectivity and to identify molecular determinants, in order to design MTDLs

Rational drug design of antineoplastic agents using 3D-QSAR, cheminformatic, and virtual screening approaches

Support was kindly provided by the EU COST Action CM1406 and CA15135. KN and JV kindly acknowledge national project number 172033 supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia.Background: Computer-Aided Drug Design has strongly accelerated the development of novel antineoplastic agents by helping in the hit identification, optimization, and evaluation. Results: Computational approaches such as cheminformatic search, virtual screening, pharmacophore modeling, molecular docking and dynamics have been developed and applied to explain the activity of bioactive molecules, design novel agents, increase the success rate of drug research, and decrease the total costs of drug discovery. Similarity searches and virtual screening are used to identify molecules with an increased probability to interact with drug targets of interest, while the other computational approaches are applied for the design and evaluation of molecules with enhanced activity and improved safety profile. Conclusion: In this review are described the main in silico techniques used in rational drug design of antineoplastic agents and presented optimal combinations of computational methods for design of more efficient antineoplastic drugs.PostprintPeer reviewe

A perspective on multi-target drug discovery and design for complex diseases

Diseases of infection, of neurodegeneration (such as Alzheimer's and Parkinson's diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists

Визначення активності холінестерази з використанням 3,3′,5,5′-тетраметилбензидину як індикаторної сполуки

Aim. To develop a new method, which has a good reproducibility of the experimental results, is fast, cheap and provides safe working conditions during the analysis, in order to determine the activity of cholinesterase.Experimental part. The light absorption of the test and control samples was measured using a CPhC-3-01 photoelectric photometer (420 nm, l = 3 cm). The reaction rate was characterized by the value of the optical density of the solution in 10 min (the fixed time method). Measurements were performed at +37 °C, the temperature of the reaction mixture was maintained by thermostatіng in water, the pH of the solutions was monitored potentiometrically using a glass electrode. The determination was repeated five times with each solution of a certain concentration of the enzyme. According to the average values obtained, the calibration graph of the specific activity of the enzyme (in international units – activity unit (AU/mg) – kmol/min to 1 mg of the substance) on the optical density of the solution was constructed. Using the mean value of five measurements of the optical density of the test solution the specific activity of the enzyme (U) was found by the calibration graph.Results and discussion. The essence of the method is the photometrical measurement of the rate of the enzymatic hydrolysis of acetylcholine in a buffer medium using 3,3′,5,5′-tetramethylbenzidine (TMB). The enzymatic hydrolysis reaction of the substrate was performed at pH 8.3, and in 10 min after the start the rate of enzymatic hydrolysis of acetylcholine was measured. The linear dependence of the optical density on the specific activity of the enzyme (U) was observed in the range of 3.5 – 28 AU/mg (activity unit/mg). The activity of the enzyme, according to the average results of 5 measurements, was 27.9 AU/mg. The declared activity the enzyme in accordance with the quality certificate was 28 AU/mg. The limit of quantification was 0.2 AU/mg. Metrological characteristics of the method were as follows: RSD = 1.8 % (n = 5; P = 0.95), accuracy – 0.45 %. These values indicate that the method proposed for determining the activity of cholinesterase is characterized by high sensitivity, reliability and reproducibility of the results. At the same time, it was proven that there was no systematic error in determining the activity of cholinesterase by the method developed.Conclusions. As a result of the research conducted a new method for determining the activity of the cholinesterase enzyme has been developed; it is characterized by high sensitivity, reliability and reproducibility of the results, and also provides safe working conditions during the analysis.Мета. Розробити новий метод визначення активності холінестерази, який має хорошу відтворюваність результатів експерименту, є швидкий, дешевий і забезпечує безпечні умови праці під час аналізу.Експериментальна частина. Світлопоглинання досліджуваного та контрольного зразків вимірювали на фотоелектричному фотометрі КФК-3-01 (420 нм, l = 3 см). Швидкість реакцій характеризували значенням величини оптичної густини розчину через 10 хв (методом фіксованого часу). Вимірювання здійснювали за +37 °C, підтримання температури реакційної суміші забезпечували за допомогою водяного термостата, рН розчинів контролювали потенціометрично за допомогою скляного електрода. Визначення оптичної густини розчину повторювали п’ять разів із кожним розчином певної концентрації ензиму. За отриманими пересічними даними будували градуювальну залежність питомої активності ензиму (у міжнародних одиницях (АО/мг) – кмоль/хв до 1 мг субстанції) від оптичної густини розчину. За пересічним з п’яти визначень значенням оптичної густини випробуваного розчину за допомогою градуювального графіка знаходили питому активність ензиму (U).Результати та їх обговорення. Суть методу полягає у фотометричному вимірюванні швидкості ферментативного гідролізу субстрату ацетилхоліну в буферному середовищі з використанням 3,3′,5,5′-тетраметилбензидину (ТМБ). Реакцію ферментативного гідролізу субстрату проводили за рН 8,3, а через 10 хвилин після початку вимірювали швидкість ферментативного гідролізу ацетилхоліну. Лінійна залежність оптичної густини від питомої активності ензиму (U) спостерігалась в інтервалі 3,5 – 28 АО/мг. Активність ензиму за пересічними результатами 5 визначень становила 27,9 АО/мг (заявлена у сертифікаті якості питома активність становить 28 АО/мг). Межа кількісного визначення – 0,2 АО/мг. Метрологічні характеристики опрацьованого способу були такими: RSD = 1,8 % (n = 5; P = 0,95), правильність – 0,45 %. Це свідчить, що запропонований спосіб визначення активності холінестерази крові характеризується високою чутливістю, достовірністю і відтворюваністю результатів. Водночас було доведено відсутність систематичної похибки під час здійснення визначення активності холінестерази опрацьованим методом.Висновки. У результаті проведених досліджень було опрацьовано новий метод визначення активності ферменту холінестерази, який характеризується високою чутливістю, достовірністю і відтворюваністю результатів, а також дозволяє забезпечити безпечні умови праці під час виконання аналізу

Polifarmakologija antagonista dopaminskih D1-receptora

Drug discovery based on development of selective ligands for a specific target intended to modulate its activity and revert pathophysiological process is now recognized as too simplistic to design effective agent for complex multifactorial diseases, characterized by diverse physiological dysfunctions caused by deregulations of complex networks of proteins. Major challenge in modern drug discovery is to rationally design multitarget drugs able to specifically modulate only a group of desired targets while minimizing interactions with off-targets. Multifactorial cerebral mechanisms implicated in mental (psychiatrics) and neurodegenerative diseases and interactions of the neurotransmitter systems are two main reasons for applying polypharmacology ('multi-target') strategy in drug discovery for these complex brain diseases. In this paper we review polypharmacological profile and potential therapeutic application of dopamine D1-like receptor antagonists.Istraživanje novih lekova koji deluju kao selektivni ligandi za određeno ciljno mesto i tako usporavaju ili zaustavljaju patofiziološki process danas se smatra nedovoljno efikasnim u razvoju lekova za kompleksna oboljenja nastala usled više patofizioloških procesa i promena u nekoliko signalnih puteva. Najveći izazov predstavlja razvoj lekova koji specifično modifikuju aktivnost nekoliko izabranih ciljnih mesta dejstva, a istovremeno minimalno stupaju u interakciju sa ostalim biomolekulima. Kompleksni patofiziološki procesi psihijatrijskih i neurodegenerativnih oboljenja i interakcija neurotransmiterskih sistema su dva ključna razloga za primenu strategije polifarmakologije (strategije multiplih ciljnih mesta) u razvoju efikasnih lekova koji deluju na centralni nervni sistem. U ovom radu dat je pregled polifarmakoloških profila i potencijalne terapijske primene antagonista receptora koji pripadaju D1 familiji dopaminskih receptora

Síntesis y evaluación farmacológica de nuevas moléculas multipotentes para el tratamiento de la enfermedad de Alzheimer

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Faculta de Ciencias, Departamento de Química Orgánica. Fecha de lectura: 28-11-201

Molecular aspects of monoamine oxidase B

Monoamine oxidases (MAO) influence the monoamine levels in brain by virtue of their role in neurotransmitter breakdown. MAO B is the predominant form in glial cells and in platelets. MAO B structure, function and kinetics are described as a background for the alterations in its activity on behavior. The need to inhibit MAO B to combat decreased brain amines continues to drive the search for new drugs. Reversible and irreversible inhibitors are now designed using data-mining, computational screening, docking and molecular dynamics. Multi-target ligands designed to combat the elevated activity of MAO B in Alzheimer’s and Parkinson’s Diseases incorporate MAO inhibition (usually irreversible) as well as iron chelation, antioxidant or neuroprotective properties. The main focus of drug design is the catalytic activity of MAO, but the imidazoline I2 site in the entrance cavity of MAO B is also a pharmacological target. Endogenous regulation of MAO B expression is discussed briefly in light of new studies measuring mRNA, protein, or activity in healthy and degenerative samples, including the effect of DNA methylation on the expression. Overall, this review focuses on examples of recent research on the molecular aspects of the expression, activity, and inhibition of MAO B.PostprintPeer reviewe

Key targets for multi-target ligands designed to combat neurodegeneration

This article is based upon work from COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”, supported by COST (European Cooperation in Science and Technology). The authors thank the participants in COST Action for productive collaborations. M. Majekova acknowledges the support of VEGA 2/0033/14, and M. Medina the support of MINECO, Spain (BIO2013-42978-P)Growing evidence supports the view that neurodegenerative diseases have multiple and common mechanisms in their aetiologies. These multifactorial aspects have changed the broadly common assumption that selective drugs are superior to ‘dirty drugs’ for use in therapy. This drives the research in studies of novel compounds that might have multiple action mechanisms. In neurodegeneration, loss of neuronal signaling is a major cause of the symptoms, so preservation of neurotransmitters by inhibiting the breakdown enzymes is a first approach. Acetylcholinesterase (AChE) inhibitors are the drugs preferentially used in AD and that one of these, rivastigmine, is licensed also for PD. Several studies have shown that monoamine oxidase (MAO) B, located mainly in glial cells, increases with age and is elevated in Alzheimer (AD) and Parkinson’s Disease’s (PD). Deprenyl, a MAO B inhibitor, significantly delays the initiation of levodopa treatment in PD patients. These indications underline that AChE and MAO are considered a necessary part of multi-target designed ligands (MTDL). However, both of these targets are simply symptomatic treatment so if new drugs are to prevent degeneration rather than compensate for loss of neurotransmitters, then oxidative stress and mitochondrial events must also be targeted. MAO inhibitors can protect neurons from apoptosis by mechanisms unrelated to enzyme inhibition. Understanding the involvement of MAO and other proteins in the induction and regulation of the apoptosis in mitochondria will aid progress towards strategies to prevent the loss of neurons. In general, the oxidative stress observed both in PD and AD indicate that antioxidant properties are a desirable part of MTDL molecules. After two or more properties are incorporated into one molecule, the passage from a lead compound to a therapeutic tool is strictly linked to its pharmacokinetic and toxicity. In this context the interaction of any new molecules with cytochrome P450 and other xenobiotic metabolic processes is a crucial point. The present review covers the biochemistry of enzymes targeted in the design of drugs against neurodegeneration and the cytochrome P450-dependent metabolism of MTDLs.Publisher PDFPeer reviewe

Scentinformatics: Mining of Structure-Odor Relationships and Scent-related Medical Effects for Mono-Molecular Odorants

In this dissertation, we address the unique challenge of establishing predictive relationshipsbetween chemical structure and scent properties of monomolecular odorants, in order to supportthe discovery of new odorants with targeted properties. This challenge is both difficult and excitingbecause unlike traditional medicinal agents tested in biological assays, scent properties arecharacterized by verbal descriptors rather than traditional quantitative metrics such as bindingconstants or dose-response curves. Thus, the stated challenge requires novel ways of quantifyingand harmonizing verbal scent descriptors of odorants to enable the use of cheminformatictechniques for scent research. In Chapter 1, we establish a natural language processing-basedtechnique for harmonizing subjective scent perception-based data. In Chapter 2, we build andvalidate Quantitative Structure-Odor Relationship models to predict standardized scent profilesfrom chemical structures. In Chapter 3, we develop a knowledge graph database that integratesbiomedical and scent-perceptual data linked to odorants, to enable the exploration of links betweenolfactory processes and biomedical phenomena. The processes detailed in the three chapters ofthis dissertation form a singular workflow designed to support odorant discovery research. Theprotocols developed in this thesis are made publicly available athttps://figshare.com/projects/AJT_Dissertation_UNC_CH_ESOP_CBMC_2022/137364.Doctor of Philosoph