Design of Novel Antagonists of Matrilysin through Advanced Pharmacophore based Virtual Screening and Molecular Dynamics Simulations
Sudheer Kumar Katari,
Research Scholar,
Sri Venkateswara Institute of Medical Sciences (SVIMS)
The study highlights on inhibitor design against the prominent zinc dependent endopeptidases (Matrilysin-MMP- 7) involved in tumor metastasis and inflammatory processes of breast, oesophagus, stomach, colon, lung, liver, pancreas and renal cell carcinomas. Activated human matrilysin was considered, due to its hydro-proteolytic activity on extra cellular matrix (ECM) proteins mainly collagens, gelatins, fibronectins and activates crucial matrix metalloproteinases (Gelatinase A-MMP- 2 and Gelatinase B-MMP- 9) zymogens for ECM degradation and leukocyte migration. Five co-crystal structures of human MMP-7 were retrieved from the protein data bank for structure based rational drug design. Five e-pharmacophores were generated for the five diverse co-crystal complexes of human MMP-7 and screened against in-house library consisting of 21 Million compounds. Four leads with good ADMET properties and better binding affinity compared to the existing co-crystal ligands were proposed through multiple docking strategies (RRD-rigid receptor docking, QPLD-quantum polarized ligand docking and IFD-induced fit docking and binding free energy calculations) from 5000 structural analogues. Further the proposed four leads were validated by receiver operative characteristic curve metrics (ROC: 0.93) using five existing inhibitors and thousand decoy molecules. Stability of MMP-7- lead1 and MMP-7- cocrystal ligand (TQJ) complex was analyzed by molecular dynamics simulations using Desmond v4.3 in natural physiological conditions for 50 ns. Lead1 – MMP-7 complex has total energy of -63647.48 kcal/mol (-63585.62), Ca RMSD of 2.09 Å (1.66), backbone RMSF of 0.89 Å (0.95) and the strong ionic bonds formed with key residue (Glu-220) which chelate with Zn to catalyse the reaction. Hence, lead1 ceases the catalysis of MMP-7 which in turn inactivate other MMPs and metastatic condition would be controlled.
|
|
