Comparative assessment of some benzodiazepine drugs based on Density Functional Theory, molecular docking, and ADMET studies (original) (raw)
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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...
Structural Analysis and Binding Modes of Benzodiazepines with Modeled GABAA Receptor Subunit Gamma-2
2014
Activation of chloride gated GABA A receptors regulates the excitatory transmission in the epileptic brain. Positive allosteric modulation of these receptors via distinct recognition sites is the therapeutic mechanism of antiepileptic agents which prevents the hyperexcitability associated with epilepsy. These distinct sites are based on subunit composition which determines binding of various drugs like benzodiazepines, barbiturates, steroids and anesthetics. The binding of antiepileptic agents to this recognition site increases the affinity of GABA A receptor for modulating the inhibitory effects of GABAinduced chloride ion flux. In the pentameric complex structure of these receptors, the α/β interface locates the binding site of agonists and the α/γ interface forms the benzodiazepine (BZD) binding site on extracellular domain. Thus the γ subunit is shown as highly required for functional modulation of the receptor channels by benzodiazepines. The present study initiates the binding analysis of chosen benzodiazepines with the modeled GABA receptor subunit gamma-2. The extracellular domain of γ subunit of human GABA A is modeled and docking studies are performed with diazepam, flunitrazepam, and chlordiazepoxide. The results revealed the binding modes and the interacting residues of the protein with the benzodiazepines.
Recent Structure Activity Relationship Studies of 1,4-Benzodiazepines
Structure activity relationship studies of 1,4-benzodiazepines have been discussed especially with their effects as antianxiety and anticonvulsants. The currently available benzodiazepines are associated with various side effects. Nowadays the purpose of these studies is to minimize side effects with these drugs. A very little alteration is possible on the benzene ring while the modification can be done on the diazepine ring. It can adopt the different conformations and in some cases some aromatic and heterocyclic rings have been fused with this part in order to see the effect of these conformation blockers on the pharmacological activity. The structure activity studies are also linked to molecular modeling studies. This is important in adding some information for the interaction of these drugs with the receptors and how this interaction can be improved.
Sumathi Publications, 2019
Epilepsy is characterized by the presence of recurrent seizures. A seizure can be defined as “an episodic disturbance of movement, feeling, or consciousness caused by sudden synchronous, inappropriate, and excessive electrical discharges in the cerebral cortex”. One in every three patients with epilepsy is probable to be severely disabled. It is continuing this scenario as an attempt to develop potent and nontoxic anticonvulsant agents. Recently discovery of benzothiazepine derivatives as an anticonvulsant agent is significant area for research in medicinal chemistry as it is free from all side effects which is shown by a developed as an anticonvulsant agent. In this paper, we have presented results of 2D, and 3D docking poses studies of a series of 300 (Three series) molecules containing 1,5-benzothiazepine pharmacophore as anti-convulsant agents. Docking analysis was utilized to predict the mechanism of action of the designed derivatives for anticonvulsant potential. All the molecules exhibited binding score in the range of -82.61 to -118.25 kcal/mol. Most active molecules from Series 1, 2 and 3 exhibited hydrogen bond interactions with LEU282B, LEU282B and LEU282B. Also for the selected standard sodium phenytoin showed the hydrogen bond interaction with LYS637A. It was noted that the docking score of 1a to 10a, 101b to 110b and 201c to 210c was almost same as that of selected standard sodium phenytoin. Protein showed hydrogen bonding with all synthesized compound showed potential against the epilepsy with GABA nergic mechanism. Keywords: Anti-convulsant; 1,5-benzothiazepine; V-Life MDS 4.3
Journal of Molecular Structure-theochem, 1999
The series of compounds investigated includes 23 benzodiazepine derivatives, some of which demonstrate anxiolytic, anticonvulsant and sedative-hypnotic properties. The series was partitioned into two classes of active and inactive compounds. Preliminary calculations of the electronic and geometry parameters were carried out to form the so-called electron-topologic matrices of contiguity (ETMC) for each compound in the series. By comparing the matrices, the molecular fragment responsible for the desired activity has been found in all ETMC of the active compounds as a common submatrix, and is called ''the activity feature''. A submatrix of the molecular fragment that is the feature of inactivity has been revealed, too. The properties of the two features have been studied and used as rules to predict the desired activity in a series of new compounds. ᭧ 1999 Elsevier Science B.V. All rights reserved.
Revista de Chimie
Benzodiazepines represents a large category of medications that were originally developed to treat anxiety disorders or issues with anxiety, seizures, and issues with sleeping. The most common drugs abused along with benzodiazepines are other benzodiazepines, prescription pain medications and alcohol. Alcohol and benzodiazepine have a synergistic depressant effect on the central nervous system. Combining alcohol with benzodiazepines can be dangerous practice even if it is engaged in only occasionally. In the present study, using molecular docking technique we followed the binding energy of benzodiazepines with benzodiazepine receptor and efficacy of the flumazenil antidote against benzodiazepine in the presence and absence of alcohol. We realized correlation study of molecular descriptors value of benzodiazepines with benzodiazepine-GABAA complex binding energy.
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. #
Electronic structure and dosage correlation of 1,4-benzodiazepines
European Journal of Chemistry, 2019
Density functional theory was used to calculate the electronic structure of 20 selected 1,4-benzodiazepine derivatives. Certain parameters were extracted from the theoretical calculations, including the proton affinity of N1, the total energy, HOMO and LUMO energies, the total positive atomic charge, dipole moment and molecular volume. These parameters were used for the correlation with the minimum effective dose acting on human. The correlation was performed by applying linear least square method. Seven parameters were found to afford good fit. Clorazepate, one of the benzodiazepines, was studied extensively, it contains a carboxylate group, which can act as an ordinary molecule or zwitterions, where the ionisable proton migrates to N1. The energy gap between the two forms was found to be strongly dependent on the solvent dielectric constant.
Study of active site and SAR of some benzodiazepines
Journal of Computational Biology and Bioinformatics Research, 2010
In the present work, efforts have been made to study the structure activity relationship as well as effect of modeling properties on psychotropic activity of benzodiazepines. The study made by using graph theoretical indices and physicochemical properties. The best model for mathematical calculation of biological activity under consideration is derived in multivariate form using multiple linear regression method and validated by variety of cross validation parameters. Effect of three dimensional features or modeling properties on biological activity were studied using modeling parameters. Finally, the study of active site has been performed by using molecular mechanics, applying MM + force field for the molecular optimization and molecule-molecule superimposing.
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.