المنھج اللغوي في التفسير و تاريخه

The Holy Quran was revealed in Arabic Language, it is, therefore necessary to seek Arabic Diction to gain the direct guidance from it. The companions of Holy Prophetr, Tabeen, and the reverent Imams strictly rebuked those interpreters who interpret the Holy Quran without having command over Arabic Language. The verses of Quran that are clear in comprehension, explicit and easy, do require the source of interpretation as “Arabic Diction”. This method highlights the positive trends to Arabic Diction. But in the matter of ambiguity and resemblance in verses and deduction of Masael, this Diction will be given second priority. Mere Diction and Arabic Socio-Diction may not be titled as most authentic. Diction is not the ‘last word. ’ The very first priority will be given to the verses of Quran, Hadith e Nabvi and Quotations of Companions of Holy Prophetr. The companions themselves were the native Arabs but they used to do consult some Quranic terms with the Holy Prophetr. As time passed, some strayed sects and atheists ignored this positive trend (Tafseer-bil-Mathur), and accustomed a new trend of interpretation of Holy Quran i. E. Depending upon Arabic Diction only so that they may endorse their own thoughts. It was a negative source of interpreting the Holy Quran i. E. Only by Arabic Diction. The present article explores its historical perspectives after evaluating its negative trends. The Motazila sect got this trend nourished. The representing interpretations of Holy Quran of this trend have been analyzed in this article. At the end, Molana Ameen Ahsan Islahi’s approach to Diction and his Tafseer ‘Tadabbur e Quran’ has been evaluated.

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.