DESIGN OF CARBONIC ANHYDRASE II INHIBITOR BASED ON NATURAL PRODUCT COMPOUNDS FROM PHENOLIC GROUP AND CURCUMIN ANALOGUES

• Main Author: ADITAMA, REZA
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/30360
• Institution: Institut Teknologi Bandung

<p align="justify">Carbonic anhydrase II (CAII) is an enzyme with a supercatalytic activity. This enzyme catalyzes a reversible reaction of CO2 into a carbonate ion and a water molecule. It also play an important roles on many metabolism process in human body such as regulation of body’s pH, electrolyte regulator, water transport process, etc. Because of many physiological process involving CAII, the deficiency or excess of this enzyme are closely related to several diseases such as <br /> glaucoma, osteopetrosis and diabetes. Glaucoma is a disease associated to high intraocular pressure in the eye that causes vision problem, even blindness. The <br /> treatment of the glaucoma is usually performed using CAII inhibitors. Sulfonamide compounds such as acetazolamide and methazolamide have been used as commercial drugs to treat glaucoma. These compounds have been shown to have strong inhibition activity against CAII. However, the use of these drugs produces many side effects such as weight loss, nausea, dizziness, etc. Therefore, the searches for novel inhibitor are still being carried out. <br /> <br /> One of the common approaches to search a novel inhibitor is by using molecular framework from natural products structure. In this study, phenolic compounds and curcumin analogues are used in the search for the novel CAII inhibitor. These two compounds have hydroxyl group at the aromatic ring. Both of phenolic and curcumin compounds are known to have anti-inflammatory and anti-cancer activity. However, research on the potential of inhibition of these compounds against CAII still has not been explored yet. Hence, searching of novel CAII <br /> inhibitor based on phenolic group and curcumin analogues that have inhibition activity against CAII has been carried out on this study. <br /> <br /> In this study, we have evaluated the potency of phenolic group to inhibit CAII. Evaluation of 40 compounds from phenolic group with docking method showed that fisetin was the best inhibitor candidate for CAII. Fitness score resulted from the docking was 51.46. This fitness score indicates that fisetin has good affinity to the CAII. Docking simulation shows that fisetin interacts with the Zn2+ ion and is stabilized by hydrogen bonding from Asn67, Thr199 and Thr200. Further analysis with molecular dynamics simulation showed that the interaction of fisetin with Asn67 and Thr200 was not observed, meanwhile the interaction of fisetin with Thr199 residue was still observed during the simulation.<br /> <br /> The screening of CAII inhibitors from curcumin analogues was also performed in this study. From 44 curcumin analogues compounds, we found six curcumin analogues that have high affinity against CAII with IC50 values within range of 7.92±0.54 ?M to 72.31±2.21 ?M. (E)-3-((E)-2-hydroxybenzylidene)-5-((2-hydroxyphenyl) methylene)piperidine-4-one or a1 has the lowest IC50 value of 7.92±0.54 ?M. Fitness score for a1 obtained from the docking simulation was 49.76. The interactions of a1 with CAII were occured between the hydroxyl group <br /> at the ortho position (R2) and the NH group at the position R1 with Gln92, Thr199 and Thr200 residues. The interaction between a1 with Thr199 and Thr200 remained stable after being evaluated by molecular dynamics simulation, meanwhile the interaction of a1 with Gln92 was not observed. <br /> <br /> <br /> We have also successfully carried out the design of new inhibitors from phenolic compounds and curcumin analogues. The structures of inhibitor candidates of <br /> CAII (fisetin and a1) were modified in silico to produce better binding affinity to the CAII. The designed compound (F12) has a better affinity against CAII <br /> compared to fisetin. The fitness score of F12 produced from docking simulation was increased from 51.46 to 55.95. The strenghtening interactions of F12 with Thr199 and Thr200 compensate the missing interaction with Zn2+ ion. A similar increase in the fitness score was also observed in 3-piperidinil-a1 and 3,3’- diamin-a1, which showed better affinity against CAII compared to a1. The fitness score of these compounds were increased from 49.76 to 54.42 and 54.89 for 3-piperidinil-a1 and 3,3’-diamin-a1, respectively. The increased affinity of 3- <br /> piperidinil-a1 is obtained from the strengthening interaction between the designed compounds with Thr199 and Thr200 residues, as well as the additional interaction with Zn2+ ion. On the other hand, the increased affinity of 3,3’-diamin-a1 gained from the strengthening interaction with Thr199 and Thr200 residues without involving covalent interaction with Zn2+. <br /> <br /> This study contributes a new insight on the systematic search, development and design of CAII inhibitors from phenolic groups and curcumin analogues. <p align="justify">