Design Of Potential Dual Acting 5HT3 Antagonist / 5HT4 Agonist For The Management Of IBS

Abstract

Irritable Bowel Syndrome is a chronic disease that affects the digestive system, causing GIT symptoms such as diarrhea, constipation or abdominal pain. It’s a highly prevalent disease worldwide, found in all countries but mostly centered in the Americas and Asia. Many solutions have been studied for this disease, but none were directed towards its treatment, but rather the relief of the symptoms. Certain drugs were proposed such as anticholinergics, antibiotics, tricyclic antidepressants, and most importantly 5HT-3 receptor antagonists and 5HT-4 receptor agonists. Unfortunately, all drugs other than the latter two did not show much success due to their side effects and lack of selectivity. We are going to be targeting 5HT-3 antagonists such as Alosetron and 5HT-4 agonists such as Tegaserod. Our focus will be mainly on Mosapride, which works as both 5HT-3 antagonist and 5HT-4 agonist, and we are going to optimize it to be more selective towards IBS with lesser side effects. On searching for the protein structure of 5HT3, there was no suitable human protein that obeys the criteria and only a mouse-one (6Y1Z) was suitable which showed high percentage matrix 84.91% upon alignment. Concerning 5H-4 protein structure search, there was no suitable one and a homology model was built and the chosen one is 5d5a.1.A. Preparation of molecules acting as both 5 HT-3 and 5 HT-4 took place, with obtaining the best poses of each following a conformational search and docking each one in its target receptor. After identifying the important functional groups that need modification in order to increase affinity of Mosapride and M1 to both 5HT-3 and 5HT-4, these modifications were applied and the best ones with the highest affinity were chosen. This is in order to optimize our molecule, Mosapride, to increase its metabolizing action and thus increasing the 5-HT3 antagonistic activity while retaining and even improving the 5HT-4 agonistic activity. By this, it two dual targeting derivatives that are effective in IBS-M type was found.