A Structure-based QSAR and Docking Study on Imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4,]benzodiazepines as Selective GABAAα5 Inverse Agonists (original) (raw)
Related papers
Structural Chemistry
In this paper, a data set of [ 3 H] diazepam derivatives was analyzed using various computational methods: molecular docking/dynamic simulations, and QSAR analysis. The main aims of these studies are to understand the binding mechanisms by which benzodiazepines allosterically modulate GABA A receptor α 1 β 2 γ 2 subtypes, from inducing neuronal inhibition at lower doses to the anesthetic effect at higher doses, and also, to define the structural requirements that contribute to improving the response of GABA A /α 1 β 2 γ 2 receptor to benzodiazepine drugs. The results of the molecular docking study allowed selecting Ro12-6377 and proflazepam as the best modulators for the four binding sites simultaneously. Subsequently, the stability of the selected complexes was investigated by performing molecular dynamics simulation. The latter confirmed the features of both modulators to exert direct effects on the chloride-channel lining residues. Pharmacokinetics and drug-likeness profile were assessed through in silico tool. Furthermore, a QSAR analysis was conducted using an improved vemolecular dynamics simulations proposed byrsion of PLS regression. The goodness of fit and the predictive power of the resulting PLS model were estimated according to internal and external validation parameters: R 2 = 0.632, R 2 adj = 0.584, F = 12.806; p-value = 6.2050e − 07, Q 2 loo = 0.639, and Q 2 F3 = 0.813. Clearly, the obtained results ensure the predictive ability of the developed QSAR model for the design of new high-potency benzodiazepine drugs.
Pharmaceuticals
Designer benzodiazepines (DBZDs) represent a serious health concern and are increasingly reported in polydrug consumption-related fatalities. When new DBZDs are identified, very limited information is available on their pharmacodynamics. Here, computational models (i.e., quantitative structure-activity relationship/QSAR and Molecular Docking) were used to analyse DBZDs identified online by an automated web crawler (NPSfinder®) and to predict their possible activity/affinity on the gamma-aminobutyric acid A receptors (GABA-ARs). The computational software MOE was used to calculate 2D QSAR models, perform docking studies on crystallised GABA-A receptors (6HUO, 6HUP) and generate pharmacophore queries from the docking conformational results. 101 DBZDs were identified online by NPSfinder®. The validated QSAR model predicted high biological activity values for 41% of these DBDZs. These predictions were supported by the docking studies (good binding affinity) and the pharmacophore modelli...
Molecular Pharmacology
A novel computer-aided receptor modeling method, REMOTEDISC [J. Med. Chem. 32:746-756 (1989)], has been used to analyze the inhibition of labeled diazepam binding by 29 benzodiazepine receptor ligands. The method uses the three-dimensional structure, conformational energy, and important atom-based physicochemical properties to model the hypothetical binding site cavity. The model not only consists of the geometry of the binding cavity but also gives the weight of the various physicochemical properties of the ligands at different parts of the binding cavity responsible for their binding to the receptor. The model fitted the binding data with a correlation coefficient of 0.980, a SD of 0.223, and an explained variance of 0.898. It suggested that a small hydrophilic group is favored at position 1 of the benzodiazepine ring, the C = O region of this ring is favored by dispersive atoms and positive charge, the 4'-substituent of the 5-phenyl group is subject to strong steric repulsion...
Journal of Medicinal Chemistry, 1997
The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910-2921 has been extended. A series of carboxamide derivatives endowed with differently substituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the carbonyl and aromatic moieties for interaction with the PBR binding site. The synthesis of most of these compounds involves Weinreb amidation of the appropriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PBR affinity similar to that shown by 1 and the presence of a basic N-ethyl-N-benzylaminomethyl group in 3-position of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational methods were used to furnish descriptors of the isolated ligands (indirect approaches) able to rationalize the variation in the binding affinity of the enlarged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributions to ligand-receptor interactions. Molecular descriptors which explicitly account for the electrostatic contribution to the interaction (CoMFA, CoMSIA, and surface approaches) perform well, but they do not improve the quantitative models. Moreover, useful hints for the identification of the antagonist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmacophoric approach. The ligand-receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestions for further experiments. Figure 10. (a) Binding site of 1 (E ) -62.09 kcal/mol). (b) Binding site of compound 8f (E ) -66.69 kcal/mol). (c) Binding site of compound 10c (E ) -62.16 kcal/mol). (d) Superimposition of the binding sites of 1, 8f, and 10c, showing the receptor flexibility.
Journal of Molecular Graphics and Modelling, 2004
A Catalyst pharmacophore model has been developed for the benzodiazepine site within the GABA A receptor complex. The model is based on a pharmacophore model originally proposed by Cook and co-workers (Drug Des. Discovery 1995, 12, 193-248) and further developed by Kahnberg et al. (J. Med. Chem. 2002, 45, 4188-4201). The Catalyst pharmacophore model has been validated by using a series of flavonoids with varying affinities for the benzodiazepine receptor and has then been used as a search query in database searching with the aim of finding novel structures which have the possibility to be modified into novel lead compounds. Five of the hits from the database searching were purchased and their affinities for the benzodiazepine site of the GABA A receptor were determined. Two of the compounds displayed K i values below 10 mM. The substance showing highest potency in-vitro displayed an affinity of 121 nM making it an interesting compound for optimization. The false positive compounds (K i values >10 mM affinities) have been analysed in terms of conformational energy penalties and possibilities for hydrogen bond interactions. The analysis clearly demonstrates the need for post processing of Catalyst hits. #
3D-QSAR Model of Flavonoids Binding at Benzodiazepine Site in GABA A Receptors
With flavone as a structural template, three-dimensional quantitative structure-activity relationship (3D-QSAR) studies and ab initio calculations were performed on a series of flavonoids. A reasonable pharmacophore model was built through CoMFA, CoMSIA, and HQSAR analyses and electrostatic potential calculations. A plausible binding mode for flavonoids with GABA A receptors was rationalized. On the basis of the commonly recognized binding site, the specific S1 and S2 subsites relating to substituent positions were proposed. The different binding affinities could be explained according to the frontier orbitals and electrostatic potential (ESP) maps. The ESP could be used as a novel starting point for designing more selective BZ-binding-site ligands. Figure 8. Electrostatic potential maps of flavone (a), 6-bromo-3′nitroflavone (b), and diazepam (c) derived from ab initio HF/ 6-31G** calculations. The blue lines represent the positive part, and the pink lines represent the negative part. The contour spacing is 0.15 au for the positive part and 0.01 au for the negative part. The units of the axes are in angstroms.
Indian journal of biochemistry & biophysics, 2006
Considering the potential of peripheral benzodiazepine receptor (PBR) ligands in therapeutic applications and clinical benefit in the management of a large spectrum of different indications, quantitative structure-activity relationship (QSAR) study has been attempted to explore the structural and physicochemical requirements for selectivity of 2-phenylimidazo[1,2-a]pyridineacetamides for binding with peripheral over central benzodiazepine receptors (CBRs). For PBR binding affinity, molar refractivity (MR) shows a parabolic relation with binding affinity suggesting that binding affinity increases with increase in volume of the compounds, until it reaches the critical value, after which the affinity decreases. The negative coefficients of S_aaN and S_ssNH indicate that binding affinity increases with decrease in E-state value of (N/) (aromatic nitrogen) and HN< (secondary amino group) fragments. The coefficient of 3XVC and JX term indicates the importance of shape and branching for...
Bioorganic & Medicinal Chemistry, 2001
AbstractÐA large number of structurally dierent classes of ligands, many of them sharing the main characteristics of the benzodiazepine (BDZ) nucleus, are active in the modulation of anxiety, sedation, convulsion, myorelaxation, hypnotic and amnesic states in mammals. These compounds have high anity for the benzodiazepine binding site (BDZ-bs) of the GABA A receptor complex. Since 1989 onwards our laboratories established that some natural¯avonoids were ligands for the BDZ-bs which exhibit medium to high anity in vitro and anxiolytic activity in vivo. Further research resulted in the production of synthetic¯avonoid derivatives with increased biochemical and pharmacological activities. The currently accepted receptor/pharmacophore model of the BDZ-bs (Zhang, W.; Koeler, K. F.; Zhang, P.; Cook, J. M. Drug Des. Dev. 1995, 12, 193) accounts for the general requirements that should be met by this receptor for ligand recognition. In this paper we present a model pharmacophore which de®nes the characteristics for a ligand to be able to interact and bind to a¯avone site, in the GABA A receptor, closely related to the BDZ-bs. A model of ā avone binding site has already been described (Dekermendjian, K.; Kahnberg, P.; Witt, M. R.; Sterner, O.; Nielsen, M.; Liljerfors, T. J. Med. Chem. 1999, 42, 4343). However, this alternative model is based only on graphic superposition techniques using as template a non-BDZ agonist. In this investigation all the natural and synthetic¯avonoids found to be ligands for the BDZ-bs have been compared with the classical BDZ diazepam. A QSAR regression analysis of the parameters that describe the interaction demonstrates the relevance of the electronic eects for the ligand binding, and shows that they are associated with the negatively charged oxygen atom of the carbonyl group of the¯avonoids and with the nature of the substituent in position 3 H . #
Medicinal Chemistry, 2009
Three dimensional quantitative structure activity relationship approach using CoMFA and CoMSIA was applied to a series of 4-quinolone derivatives as highaffinity ligands at the benzodiazepine site of brain GABA A receptors. For the purpose, 27 compounds were used to develop models. 3D-QSAR models with high-squared correlation coefficient of up to 0.979 for CoMFA and 0.931 for CoMSIA were established. The robustness of the model was confirmed with the help of leave one out cross-validation method with r cv 2 values of up to 0.526 and 0.546 for CoMFA and CoMSIA, respectively. Developed models highlighted the importance of shape of the molecules, i.e., steric descriptors for GABA A receptor binding.
2006
The structural and physicochemical requirements of 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl-acetamides for binding with peripheral benzodiazepine receptor has been explored in the present QSAR study. The calculated hydrophobicity, logP calc , shows a parabolic relation with the peripheral benzodiazepine receptor binding affinity, which suggests that the binding affinity increases with increase in the partition coefficient of the compounds until it reaches the critical value after which the affinity decreases. The range of the optimum values of logP calc is between 5.423-5.819 as found from different equations. The width of the para substituents at R 3 position is conducive for the binding affinity. The Estate values of the fragments like methyl, C , C and N are conducive for the binding affinity, while Estate value of the fragment-F is detrimental to the binding affinity. The average distance sum of the connectivity (Balaban J) among different groups is also conducive for the binding affinity. The presence of methyl groups at R 1 and R 2 positions and the presence of substituents at R 5 position are detrimental to the binding affinity, while presence of substituents at R 3 position and the presence of methyl group at R 6 position are conducive to the binding affinity.