البعد الأخلاقي في سياسة الرسول صلى الله عليه وسلم

The Arab’s tribes were diverse and were scattered all over Arabia. They were alien to any system, were unfamiliar of any rules and regulations. When the prophet PBUH came to them, He gently handled them, made them lenient, gathered them at the one true platform and eventually he was succeeded in uplifting them into the bondage of brotherhood. He guided them towards the political structure so that they can live under its shadow and follow its rules and regulations. He trained amongst them Preachers, judges, leaders and politicians. He sent his messengers to all the rulers of the worlds. These messengers were able to shake the Persians and Roman thrones which were considered the greatest empires of that time. They all got united against this newly arising force which later brought the greatest revolution in the history of humankind. The solutions presented by the Prophet PBUH while confronting the challenges in spreading his message,  enjoy the political wit, which is considered far better than the wit of political scholars and political tycoons. His ability of prior reading of the incidents, uncovers his huge potential in his prior dealing of the matters and suggesting its solutions and substitutes. His policies played a vital role in establishing the prior relations with Njashi, and later to facilitate the Muslims during their first immigration towards Abyssinia from the cruelty of the idolaters. Moreover, He chose the best time for the Treaty of Hudaybiyyah and Conquest of Mecca. He chose among his companions the one who knew the International languages and sent them as his Ambassadors to the rulers and tribal chiefs along with his written or verbal messages. He addressed the each with the method appropriate to him and suited him the best. He made best use of alliance, as he alienated the Arab tribes, from Jews and the others. In this way he was able to take a huge time to concentrate on those nations and was able to make a lot of allies. In his internal policy matters, he always tried to solve his problems, developing the society and to sabotage the malicious intentions which were planned by hypocrites, who were considered as his most dangerous enemies. His policy towards them was to admit apparently and leaving their unrevealed intentions to ALLAH. He treated them well, because he was anxious on preserving the freedom of all and the unity among his companions. When their malicious intentions started turning to become a threat to the security of Islam and started harming the interests of the society, He had not reply them strongly and dissuasively. He demolished the Mosque through which they were planning to harm the Muslim community. Moreover, he drew a line to their plans of aggression without harming anyone. He was very witty in his policies through which he was able to defeat them in the end. In this way he was able to change the course of the whole history on mankind. In this research we will try to deal with his moral wit which is considered the main characteristic of his policy.

Functional Characterization of Human Multidrug Resistance Atp-Binding Cassette Transporters

ABC (ATP-binding cassette) transporters comprise one of the largest class of transmembrane proteins. One of the most studied member of the human ABC transporters superfamily is ABCB1 which is also known as P-glycoprotein (P-gp) or multidrug resistance 1 (MDR1). Physiologically, P-gp protects the cells by exporting structurally and chemically unrelated substances out of the cell. P-gp also plays an important role in pharmacokinetics of drugs. Multidrug resistance (MDR) is a common phenomenon observed in cancer cells which is mediated by several molecular pumps including P-gp. Therefore, it is also called multidrug resistance transporter. A major problem in the treatment of diseases like cancer has been the development of resistance to chemotherapies. The present study comprises of three major sections. 1. In silico study for selection of interacting residues of human P-gp with benzophenone sulfonamide type of derivatives 2. Generation and functional characterization of mutants selected from in silico work 3. Screening of benzophenone sulfonamide derivatives for their P-gp inhibitory potential to see their effect on reversal of MDR. For in silico studies, two templates were used for molecular docking of a class of benzophenone sulfonamide derivatives in order to predict the residues in the binding pocket of human P-gp. The crystal structure of mouse P-gp (PDB: 4M1M) was used as a template to build the homology model of human P-gp. Benzophenone sulfonamides were initially docked into the modeled human P-gp. Additionally, the recently published CEM structure of humanmouse chimeric-P-gp was used to dock the same class. Docking results predicted certain important residues of the binding cavity involved in binding to benzophenone sulfonamide derivatives. Among the interacting residues tyrosine Y307 and Y310 were found directly interacting with active compounds of the benzophenone sulfonamide derivatives. Y310 was found in both the types of docking while Y307 was a major interacting partner in humanmouse chimeric structure and found in close vicinity in the modeled human P-gp structure. The second section of the thesis describes the generation of two arginine mutants Y307R and Y310R. Tyrosine Y307 and Y310 were selected for mutation on the basis of docking results. Both Y307 and Y310 were mutated to arginine to see if the mutant transporter showed any difference in transport of substrates and inhibitors including rhodamine 123, propafenone GPV31, verapamil and 3 novel benzonphenone sulfonamide derivatives. Y307R and Y310R mutants were expected to alter the binding of substrates or inhibitors and also affect the transport rate. As expected the two mutants Y307R and Y310R showed a decrease in transport of rhodamine123 which clearly demonstrated the importance of intact tyrosines at position 307 and 310 for transport activity of human P-gp for its renowned substrate rhodamine123. In addition, results with well-known inhibitor of P-gp verapamil and propafenone analogue showed that both mutants require low concentration of inhibitors to inhibit P-gp as compared to wild type transporter. When the inhibition experiments of P-gp were conducted using benzophenone sulfonamide derivatives again both mutants behaved like verapamil and propfenone analogue by showing lower IC50 values as compared to wild type transporter. It had been noticed that Y307R was equally expressed as that of wild type and Y310R showed a slight higher expression as that of P-gp which indicated that these two mutants did not mechanically alter the transporter.Third section of the thesis describes evaluation of benzophenone sulfonamide derivatives as inhibitors of P-gp. Such class of compounds were proven to be good inhibitors as they possess lower molecular weights and LopP values than the well-known inhibitor verapamil. IC50 values showing inhibitory activity of the active compounds (11, 13 and 14) in very low nanomolar range were found to be 0.029 µM ± 0.001, 0.07 µM ± 0.02 and 0.005 µM ± 0.002 respectively.