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

Molecular Considerations In The Design Of Novel Alpha/Beta Hydrolase Inhibitors

Alpha/beta hydrolases (ABHs) are a superfamily of hydrolytic enzymes that process a wide variety of substrates. A subfamily of ABHs called carboxylesterases (CEs) are important enzymes that catalyze biological detoxification, hydrolysis of certain pesticides, and metabolism of many esterified drugs. The chemotherapy drug irinotecan used for treatment of colorectal cancer is metabolized to SN-38, the active drug metabolite, by two CE isozymes CES1 (localized in the liver) and CES2 (localized in the small intestines). CES2\u27s ability to activate irinotecan at a faster rate than CES1 creates a localization of activated SN-38 in the gut epithelium, resulting in the dose limiting side effect of delayed diarrhea. Development of inhibitors for the CE subfamily of ABHs could assist in ameliorating the toxic side effects associated with some esterified prodrugs such as irinotecan, and enhance the distribution of prodrugs in vivo. Hence, our research targets CES2 for inhibitor design with the goal of amelioration of intestinal cytotoxicity associated with irinotecan chemotherapy. In this work we (i) utilized QSAR technology to design and optimize novel sulfonamide CES2 inhibitors; (ii) combined QSAR with in silico design to generate new CE inhibitor scaffolds that maintained the potency of previous CE inhibitor generations, yet had improved water solubility; and ( iii) investigated the contribution of the loop 7 in CEs to sensitizing the enzyme to inhibition by sulfonamides through docking analysis. Our QSAR model, developed using 57 sulfonamide analogs, identified several features of this class of CE inhibitor that confer their potency. Using a QSAR model, constructed using 4 classes of CE inhibitors (benzils, benzoins, isatins, and sulfonamides), as a pocket site to perform in silico design we generated several new scaffolds predicted to have good solubility and potency. This work suggests that the inner loop 7 on CE plays a role in inhibitor selectivity, and interactions with this loop should be considered in the development of selective CE inhibitors. The contributions from this work will be applicable to the design of novel ABH inhibitors, help to increase the likelihood of these drugs entering in clinical use, and ameliorate the dose-limiting side effect associated with irinotecan

3D-QSAR and Molecular Docking Studies of p-Aminobenzoic Acid Derivatives to Explore the Features Requirements of Alzheimer Inhibitors

In search of novel and more potent p-aminobenzoic acid derivatives previously evaluated as effective acetylcholinesterase inhibitors for the control of Alzheimer’s disease (AD), an integrated computational approach of three-dimensional quantitative structure–activity relationship and molecular docking were performed on a series of 20 compounds. The 3D-QSAR approach was applied to statistically study the structure-activity relationships (SAR) and had yielded good statistical significance for two high predictive models; comparative molecular field analysis (CoMFA: Q2=0.785; R2=0.936; rext2= 0.818) and comparative molecular similarity indices analysis (CoMSIA: Q2=0.831; R2=0.944; rext2= 0.931). Detailed analysis of the predictive models contour maps revealed that the hydrophobic and electrostatic fields govern the bioactivity and provided much helpful information to understand the features requirement in order to develop new potent acetylcholinesterase inhibitors. These findings were very useful for designing four novel inhibitors with enhanced activities targeting acetylcholinesterase. Through molecular docking, the newly designed compounds and compound 19 were docked on AChE as the protein target which helped to analyze the interaction characteristics and explore the binding modes at the active sites of the AChE. This work may be of utility for guiding the rational design of a new generation of acetylcholinesterase inhibitors. DOI: http://dx.doi.org/10.17807/orbital.v12i4.146

QSAR analysis on tacrine-related acetylcholinesterase inhibitors

The evaluation of the clinical effects of Tacrine has shown efficacy in delaying the deterioration of the symptoms of Alzheimer's disease, while confirming the adverse events consisting mainly in the elevated liver transaminase levels. The study of tacrine analogs presents a continuous interest, and for this reason we establish Quantitative Structure-Activity Relationships on their Acetylcholinesterase inhibitory activity. Ten groups of new developed Tacrine-related inhibitors are explored, which have been experimentally measured in different biochemical conditions and AChE sources. The number of included descriptors in the structure-activity relationship is characterized by 'Rule of Thumb'. The 1502 applied molecular descriptors could provide the best linear models for the selected Alzheimer's data base and the best QSAR model is reported for the considered data sets. The QSAR models developed in this work have a satisfactory predictive ability, and are obtained by selecting the most representative molecular descriptors of the chemical structure, represented through more than a thousand of constitutional, topological, geometrical, quantum-mechanical and electronic descriptor types.Fil: Wong, Kai Y.. Imperial College London; Reino UnidoFil: Mercader, Andrew Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: Saavedra Reyes, Laura Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Centro de Investigación y Desarrollo En Ciencias Aplicadas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: Honarparvar, Bahareh. University of Kwazulu-Natal; SudáfricaFil: Romanelli, Gustavo Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Centro de Investigación y Desarrollo En Ciencias Aplicadas; Argentina. Universidad Nacional de La Plata; ArgentinaFil: Duchowicz, Pablo Román. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico la Plata. Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas; Argentina. Universidad Nacional de La Plata; Argentin

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

An integrated approach with new strategies for QSAR models and lead optimization

Compound testing set for huAChE collected from Guo et al. (PDF 52 kb

A computational insight into acetylcholinesterase inhibitory activity of a new lichen depsidone

Acetylcholinesterase (AChE) inhibitors are yet the best drugs currently available for the management of Alzheimer's disease. The recent phytochemical investigation has led to the isolation of a new depsidone 1 with moderate AChE activity (1 mu g). This work was focused on its electronic properties analysed using commercially available programs. Both the active depsidone molecule 1 and galanthamine showed to have higher HOMO energies than the inactive depsidones 2-4, isolated from the same lichen species. However, the amino depsidone derivative 7, whose structure was proposed using computational approaches, is expected to be more active AChE inhibitor than the depsidone 1, due to the improved HOMO energy value. In addition, the molecular docking study indicated that the compound 7 has ability to make the well-known interactions of potent AChE inhibitors with the enzyme active site. The data presented herein support the design of novel AChE inhibitors based on the depsidone scaffold