Computational protocol: In-Silico Drug discovery approach targeting receptor tyrosine kinase-like orphan receptor 1 for cancer treatment

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Protocol publication

[…] The sequence for Ror1 (ID AAC50714.1) was retrieved from NCBI protein database ( Secondary structure predictions were performed by PROMOTIF and GOR4 tool. Then the 3D-structure of the protein was predicted using following servers and tools CPHModel phyre2, ps2v2, RaptorX, Modeller and I-Tasser. The structures were analyzed and validated by Prosa, and SAVES server. The most correctly modelled structure was then optimized using Schrodinger’s Protein Preparation wizard. Domains were searched using CDSearch. Then the active site of the protein was predicted with help of DogSiteScorer and Schrodinger’s siteprep, . The ligands were obtained from Zinc database. Ligprep was used to prepare the ligands after having the ligands screened for multiple scaffolds. Then the ligands were screened using Schrodinger’s HTVS. The ligands having docking score below −7 kcal/mol were analyzed on druggability parameters using Mobyl Server, .Then the ligands passing the druggability parameters were docked using AutoDockVina. Again the screening was carried out at an affinity value 10.9 and above. The screened ligands were then screened for duplication and carried forward for SP docking. Top 50 ligands obtained through screening with SP docking were docked again using XP (Extra precision) docking. Then, the protein and protein-ligand15 complex were simulated using Gromacs. Extended Simple Point Charge (SPC/E) water model and “AMBER99SB-ILDN protein” force-field was used to prepare the system. The system contained a cubic water box with protein, Cl- and Na+. The system was kept neutral by adding ions. The protein was energetically minimized for 0.1 ns before the production MD simulations of 200 ns. In similar fashion the protein-ligand complex was simulated for 20 ns. The top 300 ligands were analysed using g_mmpbsa, to obtain any probable false positives and to score better docked complexes with low energy scores. […]

Pipeline specifications

Software tools Phyre, RaptorX, I-TASSER, ProteinsPlus, LigPrep, GROMACS, g_mmpbsa
Databases NCBI Protein
Applications Drug design, Protein structure analysis
Diseases Neoplasms
Chemicals Tyrosine