True or False. The structure base assumption has been widely used in the drug discovery process for decades, yet seldom has the validity of this assumption been tested. In 2003, Sung, B., et al indicated in their research that three phosphodiesterase (PDE)-5 inhibitors, sildenafil, vardenafil and tadalafil, bind into the same PDE-5 inhibitor binding pocket with various scaffolds [5]. Sildenafil and vardenafil share similar structures with different nitrogen atoms position on the bicyclic ring and the hydrophobic group on the para- position of the distal piperazine. These differences don’t alter the binding pose of these two compounds which share almost identical binding pose with each other. Both these compounds reserve the hydrogen bond interactions with the Glu on PDE-5, the phenyl ring and the bicyclic core locates in the same position (Figure 2.1 a). Due to the similarity of structures and binding poses, they should present similar effect on PDE-5, and the experimental data verified this. However, Tadalafil, another PDE-5 inhibitor gives a different scaffold and binding orientation from sildenafil and vardenafil (Figure 2.1 b). The bicyclic ring no longer exists in this compound. Instead a 4-membered ring structure occupies the corresponding position. Experimentally, tadalafil shows similar activity as sildenafil although it differs in structure and binding pose. That is to say, there are at least two different binding models for the PDE-5 inhibitor binding site with similar function. This fact violates the second term of the structure base assumption. Under these circumstances, several questions need to be reconsidered: does the structure-base fundamental assumption always stand? If not, in which condition will it fail? In order to answer these questions and validate this assumption, a protein-ligand interaction survey was performed based on a selected protein-ligand crystal structure database. a Sildenafil (Viagra) Kd:0.5-6.6nM Vardenafil (Levitra) Kd: 0.6-0.7nM b Sildenafil (Viagra) Kd:0.5-6.6nM Tadalafil (Cialis) Kd: 0.9-6.7nM Figure 2.1 Structure and binding mode comparison among vardenafil, sidenafil and tadalafil. Sildenafil is shown in green sticks, Vardenafil is shown in magenta sticks in a and Tadalafil is shown in pink sticks in b.
True or False. Students don’t need to uphold the code of ethics or keep things confidential at the hospital.
True or False. Quality means doing the right thing right the first time with the goal of providing the best care.
True or False. Data and information processed in the information systems are proprietary and confidential.
True or False. At AACH, patients have the right to exercise their rights without coercion, discrimination, or retaliation.
True or False. Patients have the right to personal privacy, to receive care in a safe setting, to be free from all forms of abuse or harassment, and to confidentiality of their clinical records.
True or False. To activate a code or in situations of emergency you should dial 5555.
True or False. During a Phase II Code Gray, a tornado has been spotted within a 10 mile radius of hospital and all patient are to be covered with blankets/sheets with staff lying/crouching down and covering their heads.
True or False. Partial and Hospital Wide are the two types of Code Green: Evacuation.
True or False. The Class of fire that healthcare settings are least likely to experience is a Class D fire.
