Role of nitrogen containing heterocyclic compounds in acyl Co-A carboxylase carboxyltransferase: Docking with dynamic simulation studies
Role of nitrogen containing heterocyclic compounds in acyl Co-A carboxylase carboxyltransferase: Docking with dynamic simulation studies
Acyl Co-A carboxylase carboxyltransferase (AccD5) is essential for cell wall lipid biosynthesis and its disruption leads to mycobacterial death. Acyl CoA is the key regulation point for fatty acid synthesis and therefore AccD5 has become a good target for mycobacterial disease. Herein, docking and Molecular dynamic simulations with other computational techniques and softwares has been used to select the best compound. The heterocyclic compounds were indole, n-methylpiperazine, piperidine, and pyrrolidine derivatives. Among which, the docking results showed Ib5, an indole containing heterocyclic compound, as a potent inhibitor with good binding affinity with -20.23 kcal/mol of energy as compared with the standard NCI-65828 (8-amino-5-(4’-hydroxybiphenyl-4ylazo)naphthalene-2-sulfonate molecule with -19.24 kcal/mol of binding energy. Additionally, MD simulations showed less fluctuations with depiction of root means square deviation and root mean square fluctuation graphs in 2A7S-Ib5 complex. Wherein, this molecular modeling of AccD5 with Ib5 provided an insight to use it as an anti-tubercular drug. Therefore, this method has helped to prove the nitrogen containing heterocyclic compounds can be used against Mycobacterium tuberculosis.
___
- [1] WHO Global Tuberculosis Report 2018, https://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf?sequence=1&isAllowed=y (accessed in July 2018)
- [2] Brennan P J, Nikaido H. The envelope of mycobacteria. Annu Rev Biochem. 1995; 64: 29–63. [CrossRef]
- [3] Corbett E L, De Cock K M. Tuberculosis in the HIV-positive patient. Br J Hosp Med. 1996; 56(5): 200–204.
- [4] Wakil S J, Stoops J K, Joshi V C. Fatty acid synthesis and its regulation. Annu Rev Biochem. 1983;52:537–579. [CrossRef]
- [5] Cronan Jr J E, Waldrop G L. Multi-subunit acetyl-CoA carboxylases. Prog Lipid Res. 2002; 41: 407–435. [CrossRef] [6] Tong L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol. Life Sci. 62(16): 1784–1803. [CrossRef]
- [7] Heath R J, White S W, Rock C O. Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002; 58: 695–703. [CrossRef]
- [8] Lin TW, Melgar MM, Kurth D, Swamidass SJ, Purdon J, Tseng T, Gago G, Baldi P, Gramajo H, Tsai SC. Structurebased inhibitor design of AccD5, An essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2005; 103: 2072-2077. [CrossRef]
- [9] Bambeke Francoise V, Pages Jean-Marie, Lee Ving J. Inhibitors of Bacterial Efflux Pumps as Adjuvants in Antibiotic Treatments and Diagnostic Tools for Detection of Resistance by Efflux. Recent Pat Antiinfect Drug Discov. 2006; 1(2): 157–175. [CrossRef]
- [10] Vasoya S L, Chovatıa P T, Purohıt D H, Joshı H S. Green chemistry approach to the synthesis of potentially bioactive aminobenzylated Mannich bases through active hydrogen compounds. J Serb Chem Soc. 2005; 70(10): 1163–1167. [CrossRef]
- [11] Davis M S, Cronan Jr J E. Inhibition of Escherichia coli acetyl coenzyme A carboxylase by acyl-acyl carrier protein. J Bacteriol. 2001; 183(4): 1499–1503. [CrossRef]
- [12] Davis M S, Solbiati J, Cronan Jr. J E. Overproduction of acetyl-CoA carboxylase activity increases the rate of fatty acid biosynthesis in Escherichia coli. J Biol Chem. 2000; 275(37): 28593–28598. [CrossRef]
- [13] Hutchinson E G, Thornton J M. PROMOTIF-a program to identify and analyze structural motifs in proteins. Prot Sci. 1996; 5: 212–220. [CrossRef]
- [14] Schrodinger Release 2018-1: Protein Preparation Wizard. Schrodinger, LLC, New York, NY, 2018 [15] DuBay K H, Hall M L, Hughes T F, Wu C, Reichman D R, Friesner R A. Accurate Force Field Development for Modeling Conjugated Polymers. J Chem Theory Comput. 2012; 8(11): 4556–4569. [CrossRef]
- [16] Schrodinger Release 2018-1: Maestro Schrodinger, LLC, New York, NY, 2018.
- [17] ChemAxon L., Marvin Sketch 5114. 2012.
- [18] Rarey M, Kramer B, Lengauer T, Klebe G. A fast flexible docking method using an incremental construction algorithm. J Mol Biol. 1996; 261: 470–489. [CrossRef]
- [19] Bursulaya Badry D, Totrov Maxim, Abagyan Ruben, Brooks III Charles L. Comparative study of several algorithms for flexible ligand docking. J Comput Aid Mol Des. 2003; 17(11): 755–763. [CrossRef]
- [20] Bowers Kevin J, Chow David E, Xu Huafeng, Dror Ron O, Eastwood Michael P, Gregersen Brent A, Klepeis John L, Kolossvary Istvan, Moraes Mark A, Sacerdoti Federico D, Salmon John K, Shan Yibing, Shaw David E. Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters. Proceedings of the ACM/IEEE Conference on Supercomputing (SC06)2006. [CrossRef]
- [21] Schrodinger Release 2017-4: Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY. Maestro- Desmond Interoperability Tools. Schrodinger, LLC, New York, NY, 2017.