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

A two-step target binding and selectivity support vector machines approach for virtual screening of dopamine receptor subtype-selective ligands

10.1371/journal.pone.0039076PLoS ONE76

Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools

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

Design, Synthesis, Biological Evaluation And Molecular Modeling Studies Of Novel Multifunctional Neuroprotective Drugs For The Treatment Of Parkinson\u27s Disease: An Effort Towards The Improvement Of In Vivo Efficacy And Modulation Of Alpha Synuclein Aggregation Property Of The Neuroprotective Parent

DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION AND MOLECULAR MODELING STUDIES OF NOVEL MULTIFUNCTIONAL NEUROPROTECTIVE DRUGS FOR THE TREATMENT OF PARKINSON\u27S DISEASE: AN EFFORT TOWARDS THE IMPROVEMENT OF IN VIVO EFFICACY AND MODULATION OF ALPHA SYNUCLEIN AGGREGATION PROPERTY OF THE NEUROPROTECTIVE PARENT MOLECULE (D-264) by GYAN PRAKASH MODI May 2014 Advisor: Dr. Aloke K. Dutta Major: Pharmaceutical Sciences Degree: Doctor of Philosophy Parkinson\u27s disease (PD) is a progressive age-related neurodegenerative disorder of the central nervous system that is characterized by gradual loss of dopaminergic neurons in the substantia nigra region of the brain. The research from the past two decades in PD area has provided more insights into the basic pathogenetic factors of PD such as roles of oxidative stress, aggregation of α-synuclein (ASN) proteins in the form soluble toxic aggregates and fibrils, increased concentration of iron in the PD brain. Levodopa (L-DOPA) became available in 1960 for the treatment of PD and is still being considered as one of the main stream therapy. However, prolog use of L-DOPA gives rise to on and off episode along with motor fluctuations and eventual oxidation of dopamine (DA) derived from L-DOPA further facilitates neurodegeneration. It is increasingly evident that drugs aiming a single target may be inadequate for the treatment of complex diseases such as PD, which is multifactorial in nature. Thus, it is hypothesized that multifunctional drugs having multiple pharmacological activities addressing multiple pathogenic factors of PD will be effective as disease modifying agent for the treatment of this disease. Our aim in the first study was to enhance brain penetration of one of our lead molecule D-264. Our current structure activity relationship study is focused on introduction of methoxy and hydroxyl group at various positions on the accessory binding biphenyl ring of this hybrid molecule. The introduction of hydroxyl group or combination of hydroxyl/methoxy group at a suitable position could further potentiate its antioxidant and neuroprotection property. Among all synthesized compounds in the first series, compound D-433 and D-533 exhibited the highest selectivity for the D3 over D2 receptor in both binding and functional assays. Lead compounds D-433 and D-533 also exhibited potent free radical quenching property, possibly indicating antioxidant activity. The lead compounds were tested in two PD animal models. Both the compounds exhibited higher blood brain barrier crossing ability compared to parent compounds D-264. Furthermore, in MTT assay lead compounds are able to protect MN9D cells from the exposure to neurotoxin MPP+ and 6-OHDA in a dose dependent manner. Compounds D-519 and D-520 were selected as lead molecules from the second series and they exhibited nanomolar to sub nanomolar range affinity at D2/D3 receptors in the receptor binding assay and [35S]GTPγS binding assay. It was concluded from this in vivo study that both D-519 and D-520 was able to efficiently cross blood brain barrier and exhibited high in vivo agonist efficacy. D-519 and D-520 can potentially chelate with Fe(III). Furthermore, D-520 is able to reverse the ASN aggregates induced toxicity at a significant level in PC-12 cells. Finally, three dimensional quantitative structure activity relationship (3DQSAR) studies CoMFA and CoMSIA were performed. Two alignment methods (atom base and flexible) and two charge calculation methods (Gasteinger-Huckel and MOPAC) were used. The presence of carbonyl group attached to piperazine ring and hydrophobic biphenyl ring was found to be one of the most important factors responsible for the D3 selectivity over D2

Theoretical study of the interaction of agonists with the 5-HT2A receptor

The 5-HT2A receptor (5-HT2AR) is a biogenic amine receptor that belongs to the class A of G protein coupled receptors. It is characterized by a low affinity for serotonin (5-HT) and for other primary amines. Introduction of an ortho-methoxybenzyl substituent at the amine nitrogen increases the partial agonistic activity by a factor of 40 to 1400 compared with 5-HT. The present study was to analyse the QSAR of a series of 51 5-HT2AR partial agonistic arylethylamines, tested in vascular in-vitro assays on rats, at a structure-based level and to suggest ligand binding sites. The compounds belong to three different structural classes, (1) indoles, (2) methoxybenzenes and (3) quinazolinediones. Following a hierarchical strategy, different methods have been applied which all contribute to the investigation of ligand-receptor interactions: fragment regression analysis (FRA), receptor modeling, docking studies and 3D QSAR approaches (comparative molecular field analysis, CoMFA, and comparative molecular similarity index analysis, CoMSIA). An initial FRA indicated that methoxy substituents at indole and phenyl derivatives increase the activity and may be involved in polar interactions with the 5-HT2AR. The large contribution of lipophilic substituents in p position of phenethylamines suggests fit to a specific hydrophobic pocket. Secondary benzylamines are more than one order of magnitude more active than their NH2 analogs. An ortho-OH or -OMe substituent at the benzyl moiety further increases activity. Homology models of the human and rat 5-HT2AR were generated using the crystal structure of bovine rhodopsin and of the beta2-adrenoceptor as templates. The derivation of the putative binding sites for the arylethylamines was based on the results from FRA and on mutagenesis data. Both templates led to 5-HT2AR models with similar topology of the binding pocket within the transmembrane domains TM3, TM5, TM6 and TM7. Docking studies with representative members of the three structural classes suggested that the aryl moieties and particularly para-substituents in phenyl derivatives fit into a hydrophobic pocket formed by Phe2435.47, Phe2445.48 and Phe3406.52. The 5-methoxy substituents in indole and phenyl compounds form H bonds with Ser2395.43. In each case, an additional H bond with Ser1593.36 may be assumed. The cationic amine interacts with the conserved Asp1553.32. The benzyl group of secondary arylethylamines is inserted into another hydrophobic pocket formed by Phe3396.51, Trp3677.40 and Tyr3707.43. In this region, the docking poses depend on the template used for model generation, leading to different interactions especially of ortho- substituents. The docking studies with the beta2-adrenoceptor based rat 5-HT2AR model provided templates for a structure-based alignment of the whole series which was used in 3D QSAR analyses of the partial agonistic activity. Both approaches, CoMFA and CoMSIA, led to highly predictive models with low complexity (cross-validated q2 of 0.72 and 0.81 at 4 and 3 components, respectively). The results were largely compatible with the binding site and confirm the docking studies and the suggested ligand-receptor interactions. Steric and hydrophobic field effects on the potency indicate a hydrophobic pocket around the aryl moiety and near the para position of phenyl derivatives and account for the increased activity of secondary benzylamines. The effects of electrostatic and H-bond acceptor fields suggest a favourable influence of negative charges around the aryl moiety, corresponding to the increase in potency caused by methoxy substituents in 2-, 4-, 5- and 6-position of phenethylamines and by the quinazolinedione oxygens. This is in accord with the role of Ser1593.36 and Ser2395.43 as H bond donors. At the benzyl moiety, the negative charge and the acceptor potential of 2-hydroxy and -methoxy substituents is of advantage. Agonists stabilize or induce active receptor states not reflected by the existing crystal structures. Based on models of different rhodopsin states, a homology modeling and ligand docking study on corresponding 5-HT2AR states suggested to be specific to agonist and partial agonist binding, respectively, was performed. The models indicate collective conformational changes of TM domains during activation. The different 5-HT2AR states are similar with respect to the amino acids interacting with the arylethylamines, but show individual topologies of the binding sites. The interconversion of states by TM movements may be accompanied by co-translations and rotations of the ligands. In the case of the secondary amines considered, the tight fit of the benzyl substituent into a hydrophobic pocket containing key residues in TM6 probably impedes the complete receptor activation due to inhibiting the rotation of this helix. High affinity of a partial agonist is therefore often at the expense of its ability to fully activate a receptor

Development of Virtual Screening and In Silico Biomarker Identification Model for Pharmaceutical Agents

Ph.DDOCTOR OF PHILOSOPH

Dopamine D3 receptor ligands—Recent advances in the control of subtype selectivity and intrinsic activity

AbstractVarious pharmacological studies have implicated the dopamine D3 receptor as an interesting therapeutic target in the treatment of different neurological disorders. Because of these putative therapeutic applications, D3 receptor ligands with diverse intrinsic activities have been an active field of research in recent years. Separation of purely D3-mediated drug effects from effects produced by interactions with similar biogenic amine receptors allows to verify the therapeutic impact of D3 receptors and to reduce possible side-effects caused by “promiscuous” receptor interactions. The requirement to gain control of receptor selectivity and in particular subtype selectivity has been a challenging task in rational drug discovery for quite a few years. In this review, recently developed structural classes of D3 ligands are discussed, which cover a broad spectrum of intrinsic activities and show interesting selectivities

Exploring 3D structure of human gonadotropin hormone receptor at antagonist state using homology modeling, molecular dynamic simulation, and cross-docking studies

Human gonadotropin hormone receptor, a G-protein coupled receptor, is the target of many medications used in fertility disorders. Obtaining more structural information about the receptor could be useful in many studies related to drug design. In this study, the structure of human gonadotropin receptor was subjected to homology modeling studies and molecular dynamic simulation within a DPPC lipid bilayer for 100 ns. Several frames were thereafter extracted from simulation trajectories representing the receptor at different states. In order to find a proper model of the receptor at the antagonist state, all frames were subjected to cross-docking studies of some antagonists with known experimental values (Ki). Frame 194 revealed a reasonable correlation between docking calculated energy scores and experimental activity values (|r| = 0.91). The obtained correlation was validated by means of SSLR and showed the presence of no chance correlation for the obtained model. Different structural features reported for the receptor, such as two disulfide bridges and ionic lock between GLU90 and LYS 121 were also investigated in the final model. © 2016, Springer-Verlag Berlin Heidelberg