تاویل نصوص کی شرعی حیثیت

The two fundamental sources of Islam are the Qur’an and Sunnah (Life) of the Hope Prophet (peace be upon him). Rulings and Legal interpretation are based in light of these two sources, and these two sources are used to determine the correct way of living. Some rulings are clear cut and explicit without any need for interpretation, while other rulings are not so clear cut and are very vague and open to multiple interpretations. Sometimes, in order to understand these vague rulings, there is a need to use different construed methods of interpretations, so that these commandments can become easier to understand and explain. The meaning of construed here is to use those interpretations which is not used commonly in order to explain the verse of life style of the beloved messenger. However, this is not something that any average human being can do, rather one must be a scholar of the highest caliber and have expertise in the field of interpretation. Additionally, the construed interpretation must be valid according to the principles of interpretation, and must have been used before in a previous interpretation. One other thing to note here is that there are many different types of taweel i.e construed interpretations. Some are correct while others are incorrect. This is why it is important to know and understand the correct use of construing and non-construing interpretations in the field of Islamic jurisprudence, so that one can differentiate between the two. Another tragedy of today is that every person thinks that they should and do have the ability to interpret the Qu’ran and the Sunnah on their own, and without any expertise in interpretation, come up with and begin to interpret the Qur’an on their own. This results in wrong interpretations, which not only misguides the individual, but countless others as well. This is a fact that the many different sects in Islam considered deviant by the majority, they all have begun with incorrect and deviant understandings and interpretations on the sacred texts in Islam.

Combined Ligand and Structure Based Studies on Modulators of Akt Kinases

Protein kinase B (PKB/Akt) belongs to the AGC superfamily of related serine/threonine kinases with three structurally homologous mammalian isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ). Akt isoforms emerged as anti-cancer drug targets because of their constitutive hyperactivation in various oncological disorders. However, due to high intra-family similarity within ATP binding region, the development of isoform-selective modulators of Akt represent a challenging endeavor and thus, until now only a handful of compounds were selected for the clinical investigation. Yet none of them could reach the market for routine clinical use due to their off-target toxicity and poor pharmacokinetic properties. Recent reports on achieving isoform selectivity by designing inhibitors against less conserved pleckstrin homology (PH) domain offer the opportunity to reduce the major off-target toxic effects of Akt antagonists. Therefore, in this thesis, combined ligand- and structure-based in silico strategies have been utilized to probe the key structural features for the inhibition of the PH domain of Akt2 which is more commonly overexpressed in solid tumors. Toward this end, various predictive 2DQSAR (two-dimensional quantitative structure-activity relationship) and GridIndependent Molecular Descriptor (GRIND) and pharmacophore models using structurally diverse data set of 111 quinoline analogs have been developed. Our key findings demonstrate that the presence of three hydrogen bond donors (D1-D3) at a molecular distance of ~8.4, 21.6, 16.8 Å between D1–D2, D1–D3 and D2–D3, respectively is important for selective inhibition of PH domain of Akt2. In addition, our docking results indicated a crucial role of Lys30 for the optimal fit of quinoline-type inhibitors within the binding cavity of the Akt2 PH domain. Moreover, the structurebased pharmacophore model exhibited three hydrogen bond acceptors (A1-A3) at a distance of 4.05 Å (A1-A2), 11.58 Å (A2-A3) and 15.33 Å (A1-A3) that are complementary to the molecular distances identified by GRIND which further validate the reliability of our developed models. Additionally, identified hits through pharmacophoric-based virtual screening provided a new arsenal of potentially selective chemical scaffolds which have a broad structural diversity and less chemical similarity to any of the other known Akt2-PH domain inhibitors. Subsequently, selectivity profiling with the help of proteochemometric modeling revealed essential substructures such as Nmethylpent-3-en-2-amine for selective inhibition of Akt1, methylene amine, isoproenylterazol and 2H-tetrazole for Akt2, and formaldehyde hydrazine for the Akt3 selective inhibition. The present work also illustrates the substructure based similarity search of ChemBridge database to identify Akt2-selective hit compounds. In the present study, one of the selected carboxamide-type hit showed 1.2 and 2.1 fold selectivity against Akt2 as compared to Akt1 and Akt3, respectively. Overall, the work described in this thesis could pave the way towards the identification of potential modulators of Akt2 against cell proliferation in cancer with high isoform-selectivity and limited side effects.