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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Identification of potential inhibitors for AroG against Mycobacterium tuberculosis

Infections by opportunistic bacteria have significant contributions to morbidity and mortality in humans. Tuberculosis has many manifestations affecting bone, central nervous system and many other organ systems. Tuberculosis is primarily a pulmonary disease that is initiated by the deposition of Mycobacterium tuberculosis (M. tb) contained in aerosol droplets onto lung alveolar surfaces. Developing potent inhibitors is an important strategy to tackle the pathogenecity of M. tb strains. Fourteen crystal structures of Phospho-2-dehydro-3-deoxyheptonate aldolase (AroG) are available in the protein data bank (PDB). AroG of M. tb possess 3 co-crystal structures (2B7O, 3NV8 and 3PFP) with substrate (PEP) and inhibitor (O35) in the PDB. Among the two diverse co-crystal structures (3NV8 and 3PFP), the best resolution structure (3NV8) was considered for structure based drug design to propose antagonists through swiss similarity screening, dockings and molecular dynamics simulations. O35 and PEP of AroG were screened against swiss similarity search of thirtyone databases comprising 31,11,77,426 compounds obtained 2858 structural hits. The hits were processed through rigid receptor docking (RRD), quantum polarized ligand docking (QPLD) and binding free energies were calculated by Prime-MM/GBSA approach (Madhulitha et al., 2017) with AroG. RRD followed by MM-GBSA calculations to the generated library of AroG resulted 29 compounds, upon comparison with crystal ligands 11 compounds were scored better. To define the leads, 11 compounds were subjected to QPLD and binding free energy calculations revealed 5-leads on comparison with PEP and O35, lead1 possess the least binding free energy and better binding affinity. Lead1 and PEP have QPLD XP Gscore of -8.490 kcal/mol and -6.487 kcal/mol, ΔGscore of -51.80 kcal/mol and -35.209 kcal/mol respectively. The stability of AroG-lead1 complex was better than AroG-PEP complex in natural physiological conditions using Desmond v5.3 for 100 ns molecular dynamics simulations (Katari et al., 2016 and Pasala et al., 2018) revealed the least potential energy (-179483.298 kcal/mol), protein backbone RMSD (3.1183 Å), protein backbone RMSF (1.1317 Å), lead1 RMSD (2.8421 Å), lead1 RMSF (0.9607 Å) with 15,031 protein-ligand contacts. The proposed lead1 possess favourable ADME/T properties and acts as the best AroG antagonist of M. tb.

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NRM is highly acknowledged to ICMR for sanctioning SRF (ISRM/11(21)/2017). Authors are thankful to DBT, Ministry of Science and Technology, Government of India, New Delhi for supporting the work through BTISnet BIF program (No. BT/ BI/25/037/2012).

References
    Madhulitha NR Pradeep N, Sandeep S, Hema K, Chiranjeevi P, et al. (2017). E-Pharmacophore Model Assisted Discovery of Novel Antagonists of nNOS. Biochem Anal Biochem 6:307. doi: 10.4172/2161-1009.1000307

    Katari SK, Natarajan P, Swargam S, Kanipakam H, Pasala C, Umamaheswari A (2016). Inhibitor design against JNK1 through e-pharmacophore modeling docking and molecular dynamics simulations. J Recept Signal Transduct Res.; 36(6): 558-571.

    Pasala C, Chilamakuri CSR, Katari SK, Nalamolu RM, Bitla AR, Umamaheswari A (2018). Epitope-driven common subunit vaccine design against H. pylori strains. Journal of Biomolecular Structure and Dynamics. doi: 10.1080/07391102.2018.1526714.

Nalamolu Ravina Madhulitha*
Katari Sudheer Kumar
Chiranjeevi Pasala
Sivaranjani Pakala
Amineni Umamaheswari**

Bioinformatics Centre
Department of Bioinformatics
Sri Venkateswara Institute of Medical Sciences University
Tirupati, Andhra Pradesh 517507 India

**Email: svims.btisnet@nic.in
*Email: ravinamadhulitha@gmail.com