20th-banner-rev.png

Albany 2019: 20th Conversation - Abstracts

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

Potent MMP-14 antagonist design through screening, docking and dynamics studies

Matrix metalloproteinase-14 (MMP-14) or membrane type MMP-1 is an extra cellular matrix (ECM) protease activates progelatinase A (MMP-2) involved in proteolysis of collagen, gelatin, elastin, laminin, fibronectin and integrins for cancerous cell to invade and metastasise. About 2,756 inhibitors from CLRI-MMpi database were retreived, optimized and minimized through LigPrep using OPLS3 forcefield. The ligands were passed through virtual screening workflow (VSW) protocol, where the ligands were refined and docked by high throughput virtual screening [HTVS-10%], standard precision [SP-10%] and extra precision [XP-100%] over the Grid of MMP-14 (5H0U) using grid based ligand docking with energetics (GLIDE) and binding free energy (ΔG) was estimated by Prime-MM/GBSA for 27 dock complexes (Chiranjeevi et al., 2016). The best bound MMpi database inhibitors (MMpI1999248, MMpI2009210 and MMpI200383) were screened against SwissSimilarity databases comprising ̴ 0.3 Billion compounds resulted 2756 structural analogues. 28 compounds were obtained from VSW, fourteen compounds were better scored (XP G and ΔG) than the best three MMpi. These were redocked by quantum polarized ligand docking (QPLD) and resulted 5 leads; the best lead (lead 1) possesses QPLD XP Gscore of -8.711 kcal/mol and ΔG score of -67.035 kcal/mol, but the best MMpi (MMpI1999248) possesses QPLD XP Gscore of -6.092 kcal/mol and ΔG score of -66.538 kcal/mol (Madhulitha et al., 2017). The best lead and the best MMpi (MMpI1999248) MMP-14 complexes were simulated for 100 ns and the dynamics were assessed for stability by analyzing root-mean-square-deviation (RMSD), root-mean-square-fluctuation (RMSF), total energy (T.E.), potential energy (P.E.), protein-ligand contacts (hydrogen bond, pi-cation, hydrophobic, metal co-ordination and water bridges), radius of gyration and torsions (Katari et al., 2016). Lead 1-MMP-14 complex showed T.E. and P.E. of -64,432.622 kcal/mol and -78,558.567 kcal/mol lesser than MMpI1999248-MMP-14 complex with -64,405.771 kcal/mol and -78,552.540 kcal/mol. Lead 1 with respective to protein and lead 1 with respective to lead 1: average RMSD was 2.16 Å and 0.68 Å, average RMSF was 0.99 Å and 0.38 Å lesser than the MMpI1999248 with respective to protein and with respective to itself: average RMSD was 5.50 Å and 2.75 Å and average RMSF of 2.26 Å and 1.85 Å were observed during 100 ns molecular dynamics (MD) simulations. The overall molecular contacts formed by MMP-14-lead 1 (9,745) are comparatively higher than MMP-14-MMpI1999248 (9,482) in 100 ns MD simulations suggested that lead 1 could act as a potent antagonist by blocking the functional activity of MMP-14, MMp-2 activation, ECM degradation, cancer cell invasion as well as metastasis.

katari-fig.gif

KSK is highly acknowledged to DBT for sanctioning JRF and SRF (BT/ BI/25/037/2012). 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
    Chiranjeevi P, Swargam S, Pradeep N, Hema K, Kumar KS, et al. (2016). Inhibitor Design for VacA Toxin of Helicobacter pylori. J Proteomics Bioinform 9: 220-225. doi: 10.4172/jpb.1000409.

    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.

Katari Sudheer Kumar*
Pasala Chiranjeevi
Nalamolu Ravina Madhulitha,
Vankadoth Umakanth Naik
Amineni Umamaheswari**

Bioinformatics Centre
Department of Bioinformatics
SVIMS University
Tirupati-517507, AP, India

*Email: katari319@gmail.com
**Email: svims.btisnet@nic.in