Drug discovery and computational strategies in the multitarget drugs era

The pharmaceutical industry is increasingly joining chemoinformatics in the search for the development of new drugs to be used in the treatment of diseases. These computational studies have the advantage of being less expensive and optimize the study time, and thus the interest in this area is increasing. Among the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due to the improvement in the quality of treatment involving several drugs. Multitarget therapy is more effective than traditional drug therapy that emphasizes maximum selectivity for a single target. In this review a multitarget drug survey was carried out as a promising strategy in several important diseases: neglected diseases, neurodegenerative diseases, AIDS, and cancer. In addition, we discuss Computer-Aided Drug Design (CADD) techniques as a tool in the projection of multitarget compounds against these diseases

A Smo/Gli multitarget hedgehog pathway inhibitor impairs tumor growth

Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition

Computational polypharmacology comes of age

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N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor

On the basis of N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (II, ASS234) and QSAR predictions, in this work we have designed, synthesized, and evaluated a number of new indole derivatives from which we have identified N-methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine (2, MBA236) as a new cholinesterase and monoamine oxidase dual inhibitor.PostprintPostprintPeer reviewe

The current status of pharmacotherapy for the treatment of Parkinson's disease: transition from single-target to multitarget therapy

Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons. Motor features such as tremor, rigidity, bradykinesia and postural instability are common traits of PD. Current treatment options provide symptomatic relief to the condition but are unable to reverse disease progression. The conventional single-target therapeutic approach might not always induce the desired effect owing to the multifactorial nature of PD. Hence, multitarget strategies have been proposed to simultaneously target multiple proteins involved in the development of PD. Herein, we provide an overview of the pathogenesis of PD and the current pharmacotherapies. Furthermore, rationales and examples of multitarget approaches that have been tested in preclinical trials for the treatment of PD are also discussed

Multitarget drug design strategy in Alzheimer’s disease: focus on cholinergic transmission and amyloid-β aggregation

Background: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network. Results: By exploiting the multitarget approach, the present study provides new molecules able to target the cholinergic pathway, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit Aβ aggregation. Conclusions: These new compounds emerged as a suitable starting point for a further optimization process

Aktiivsete ühendite disain neurodegeneratiivsete haiguste raviks

Väitekirja elektrooniline versioon ei sisalda publikatsiooneNeurodegeneratiivsed haigused on tänapäeval kujunenud keskseks meditsiiniliseks ja sotsiaalseks probleemiks. Ühest küljest on selle põhjuseks haigustega kaasnevad rasked füüsilised ja vaimsed puuded ning mõjusate ravimeetodite puudumine. Teisalt on valdav enamus neurodegeneratiivseid haigusi seotud vananemisega. Oodatava eluea märkimisväärne pikenemine on põhjustanud patsientide arvu olulist kasvu. Üks peamisi takistusi neurodegeneratiivsete häirete jaoks radikaalsete ravimeetodite leidmisel on uute ravimite väljatöötamise protsessi pikkus ja kulukus. Viimase kümnendi jooksul on aga molekulaarse modelleerimise ja tehisintellekti arvutusmeetodite kaasamine võimaldanud märkimisväärselt lühendada nii uute ravimite väljatöötamiseks kuluvat aega kui ka maksumust. Käesolevas väitekirjas rakendati mitmesuguseid arvutipõhiseid ravimite otsimise meetodeid uute potentsiaalsete aktiivsete keemiliste ühendite väljatöötamiseks neurodegeneratiivsete haiguste raviks. Kaasaegsete arvutikeemia molekulaarsildamise ja molekulaardünaamika meetodite abil sõeluti virtuaalselt suuri keemiliste ühendite andmebaase, leidmaks neurodegeneratiivsete haigustega seotud valkudele toimivaid aineid. Nii tehti kindlaks rida uusi looduslikke ühendeid, mis toimivad erinevate ensüümvalkude inhibiitoritena, aga ka uudne ühend, mis toimib efektiivselt samaaegselt kahele Alzheimeri tõvega seotud valgule. Üks peamisi neurodegeneratiivsete haiguste tekke põhjusi on nn närvikasvufaktorite puudulikkus neuronites. Seetõttu on väga huvitavaks ja perspektiivseks suunaks keemiliste ühendite leidmine, mis käituksid analoogselt nende faktoritega ning kaitseks närvirakke suremise eest. Käesoleva töö käigus uuriti erinevate arvutusmeetodite abil põhjalikult ühe taolise närvikasvufaktori (gliia närvikasvufaktor GDNF) toimemehhanismi ning ennustati seda faktorit imiteeriv aktiivne ühend. Kuigi selle eksperimentaalselt mõõdetud neuroneid kaitsev toime ei vasta veel ravimitele esitatavatele nõutele, on siiski tegemist esimese sellelaadse ühendiga maailmas, mille alusel oleks võimalik välja arendada täiesti uut tüüpi ravimeid nii Parkinsoni kui ka Huntingtoni tõve raviksToday, neurodegenerative diseases are one of the most acute medical and social problems. This is due to both severe physical and mental disabilities resulting from the constant progression of the process, and the age-dependent nature of the vast majority of neurodegenerative diseases. The current accelerating increase in life expectancy inevitably leads to a significant increase in the number of such patients. There is currently no radical treatment for neurodegenerative disorders. One of the main obstacles to finding effective drugs is the length and cost of the process of developing a new drug. However, the development of modern molecular modelling and artificial intelligence methods has substantially shortened the time to dispense new medicines and reduced their cost. This dissertation provides examples of the use of various methods of computer-aided drug design such as molecular docking and molecular dynamics to develop new potential candidates against neurodegenerative diseases. The high-throughput virtual screening of large molecular libraries enabled to identify effective compounds against target proteins related to neurodegenerative diseases. In result, a series of natural compounds acting as inhibitors to enzymes related to different diseases was established. Notably, a fully novel compound acting against two proteins related to Alzheimer’s disease was predicted and experimentally verified. One of the main causes of the neurodegeneration is the mostly age-related deficiency of so called neurotrophic factors. Small molecules that can mimic the activity of these factors in cells would be thus very attractive novel drug candidates. In the present thesis, the computational modelling was used for detailed study of the mechanism of action of one of the most important neurotrophic factors (glial cell-derived neurotrophic factor GDNF). The results of this study enabled to develop first time a compound that acted similarly to this factor itself. Whereas the experimentally measured activity of this compound was moderate, it creates a basis for the development of fully new type of drugs against Parkinson’s and Huntington’s diseases.https://www.ester.ee/record=b535990

A new strategy for multitarget drug discovery/repositioning through the identification of similar 3D amino acid patterns among proteins structures: The case of Tafluprost and its efects on cardiac ion channels

The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.This research was funded by the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grants numbers 1191133, 1170662 and from Spanish Ministry of Economy and Competitiveness (projects SEV-2015-0493 and TIN2015-65316-P, grant BES-2016-078046), and from Generalitat de Catalunya (contracts 2017-SGR-1414 and 2017-SGR-1328). The financial support by DICYT-USACH grant 5392102RP-ACDicyt is also acknowledged. The web-server is hosted in the cluster obtained with the grant CONICYT-FONDEQUIP-EQM160063.Peer ReviewedPostprint (published version

Meeting report : Neuropathology and Neuropharmacology of Monoaminergic systems

The third EU 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” Annual Conference entitled “Neuropathology and Neuropharmacology of Monoaminergic Systems” was hosted by the University of Bordeaux, France on 8-10 October 2014. The conference, organized by Prof. De Deurwaerdère, was supported by COST (European Cooperation in Science and Technology) and LABEX (LABEX Brain, University of Bordeaux). The program took the form of a three-day meeting, comprising a series of French and international invited talks and breakout sessions designed to identify key gaps in current knowledge and potential future research questions. The aims of this Conference were two-fold: 1. To identify the current state-of-the-art in the understanding of the pathological mechanisms that contribute to different neuropsychiatric disorders, and to what extent, monoamines a multi-target drugs and/or other interventions might prevent these changes. 2. To identify specific areas of research where information is sparse but which are likely to yield data that will impact on future strategies to treat neurodegenerative disorders.peer-reviewe