Virtual binding of flavonoids to mycolic acid cyclopropane synthase PcaA of Mycobacterium tuberculosis using the Autodock software

Date

3-2007

Degree

Bachelor of Science in Chemistry

College

College of Arts and Sciences (CAS)

Adviser/Committee Chair

Ernesto J Del Rosario

Co-adviser

Dolores P. Buquiran

Committee Member

Jelynne P. Tamayo

Abstract

Molecular docking of flavonoids to Mycolic Acid Cyclopropane synthase (MACS) PcaA was studied using AUTODOCK software. The three-dimensional structure of MACS PcaA was obtained from RCSB Protein Data Bank. Fifty-seven naturally occurring flavonoids were docked to PcaA. Visual Molecular Display (VMD) was used to determine and view the residues involved in the binding of ligand to the enzyme. Validation of the method used was done through control docking and the free energy of binding was validated relative to literature values. The HIV 1 protease was docked to SKF 107457 and obtained energies were compared with the experimental value of -10.56 kcal/mol. T-test performed infers no significant difference in the computed binding energies compared to the experimental values at 10% level of significance. For validation of binding site determination, didecyldimethylammonium bromide (DDDMAB) was docked to the crystal structure of PcaA. The PcaA was initially unbound of any substrate analogs and the DDDMAB was obtained from the crystal structure of CmaA2. The DDDMAB acted as a reference ligand. The position where it docked was considered the inhibitors' binding site. In the main docking simulation, blind docking was implemented. The results showed that the not all flavonoid classes are potent inhibitors of PcaA. The docking energies of the flavonoids (anthocyanidins, flavones, flavans, leucoanthocyanidins and isoflavonoids) were screened and 23 of these have docking energies higher than that of the reference compound. The docked structures of the remaining 23 enzyme-ligand complex were further examined. The binding sites were viewed and the data exhibited that only 12 out of the 23 ligands bind into the active site of the enzyme. These 12 flavonoids were considered competitive inhibitors since they assumed the orientation of DDDMAB in the binding site of PcaA. The top two flavonoids, namely Jamaicin and Clandestacarpin, had the most negative energies among all the competitive inhibitors. The residues involved in the ligand-receptor interaction of Jamaicin are ASP 17, TYR 33. SER 34, LEU 95, SER 96, GLN 99, GLY 137. OLD 140, HIS 141, ILE 169, ILE 199. PHE 200, PRO 201, TYR 232, TRP 239 and TYR 265. On the other hand, Clandestacarpin interacts with residues: ASP 17, TYR 33, SER 34, LEU 95, SER 96, GLU 140. HIS 141, ILE 169, ILE 199. PHE 200. PRO 201, GLY 202, GLY 203, TYR 232, TRP 239. TYR 262 and TYR 265. All of the interactions present in the ligands fall under the range of hydrophobic interactions (3-4.5 A).

Language

English

Location

UPLB Main Library Special Collections Section (USCS)

Call Number

LG 993.5 2007 C4 G85

Document Type

Thesis

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