تاريخية السنة بين المثبتين والنافين

A group of contemporary rationalists have repeatedly maintained that the rulings derived from the Sunnah have a historical framework that does not transcend them. After being proved, they must remain locked in the time in which they were said, and we are not obliged to follow them. The prophetic interpretation of the Qur'anic text is not the only interpretation, Is one possible form of interpretation. The rationalists market some evidence of this, including: copies, reasons for descent and causes of roses, and the language of some Koranic verses. In this research we will discuss the issue of this issue, and the statements of the parties and their evidence.

Molecular Modeling Strategies to Design Novel Inhibitors of Gat1

Human γ-Aminobutyric acid (GABA) transporters (hGATs) including GAT1-3, and betaine/GABA transporter 1 (BGT1) belong to the superfamily of Na+/Cl--dependent co-transporters. Among hGATs, malfunctioning of the hGAT1 during GABA reuptake process has been associated with several neurological disorders. Therefore, hGAT1 represents a promising drug target for the development of new drug candidates against neurological disorders particularly epilepsy. At present crystal structure of hGAT1 is not determined due to the unavailability of appropriate quantities of pure and stable transporter proteins. Also the order of binding of co-transport ions (Na+ and Cl-) in hGAT1 remained gloomy. Due to high structural and functional similarity among hGATs subtypes, only handful of compounds could meet the selectivity and affinity against hGAT1. Until very recent, Tiagabine represents the only hGAT1 selective marketed drug in the last four decades. However, Tiagabine therapy has been associated with certain side effects including sedation, tremor and ataxia. This necessitates to understand the molecular basis of interactions and transport mechanism of hGAT isoforms in general and hGAT1 in particular for further identification of hGAT1 modulators. Therefore, in this project, combined ligand and structure based in-silico strategies have been utilized to identify the key structural features of hGAT1 antagonists required to modulate the hGAT1 activity, binding pattern of substrate and inhibitors in built hGAT1 model, ion transport mechanism through hGAT1, and stereo-selectivity of Tiagabine in hGAT1 followed by structure based similarity search. 3D structural features of hGAT1 modulators were evaluated by GRIDIndependent Molecular Descriptor (GRIND) analysis using multiple binding conformations of structurally diverse classes of hGAT1 modulators. Our final GRIND model demonstrated that two hydrogen bond acceptors (N1-N1) at a mutual distance of 8.00-8.40 Å, one hydrogen bond donor (O) at a distance of 5.60-6.00 Å from a hydrogen bond acceptor (N1) and one hydrophobic (DRY) group at a distance of 10.40-10.80 Å from a hydrogen bond acceptor (N1) group within a chemical entity may play an important role in achieving high inhibitory potency and selectivity against hGAT1. Our structure activity Abstract 2 relationship (SAR) data elucidate the importance of COOH group within the core structure of the hGAT1 modulators. Overall, three orders of magnitude decrease in the biological activity has been observed in the compounds where COOH group was replaced with isoxazol ring. This was further strengthened by our docking results that illustrated the interaction of COOH and –NH group within the core structure of hGAT1 with amino acid residues G65, Y140 and F294, respectively. Current work also proposes the sequential order and role of co-transported ions during the translocation cycle of hGAT1 by molecular dynamics simulations (MD). It was observed that preloading of Na+ ion at the Na1 site in the hGAT1 binding pocket helped to maintain the open-to-out conformation of hGAT1 as compared to the Na2 site. In addition, Cl- ion preloading was found necessary for the translocation process to occur in eukaryotes. Overall, the fully loaded hGAT1 i.e., two Na+ ions, one Cl- ion and a GABA molecule provided the preferred preloaded state for the reuptake transport process in our proposed mechanistic cycle of hGAT1. Furthermore, interaction profiling of most stable binding conformation of Tiagabine stereoisomers during 100 ns MD simulation revealed that protonated -NH atom of Tiagabine in R-conformation and COOH group attached at the piperidine ring of Tiagabine in equatorial configuration provided maximum strength in terms of selectivity to block flipping of hGAT1 to open-to-in conformation with thiophene rings occupying their position in hydrophobic cavity of hGAT1. The selected Tiagabine enantiomer was used for structure based similarity search to identify potential modulators of hGAT1 showing overlapping interactions profile with Tiagabine. Overall, the project provides a rationale to design potential antagonists against hGAT1 for regulating the fast inhibitory neurotransmission across the CNS. It also provides a benchmark to computationally elucidate each of the reaction steps involved in the translocation of GABA along with the cotransported ions.