DOI: 10.5061/dryad.ttdz08m4m
title: Molecular dynamics dataset for pharmacological repositioning in the treatment of non-small-cell lung cancer

description: Non-small cell lung cancer (NSCLC) is a type of lung cancer associated
 with translocation of the EML4 and ALK genes on the short arm of
 chromosome 2. This leads to the development of an aberrant protein kinase
 with a deregulated catalytic domain, the cdALK+. Currently, different ALK
 inhibitors (iALKs) have been proposed to treat ALK+ NSCLC patients.
 However, the recent resistance to iALKs stimulates the exploration of new
 iALKs for NSCLC. Here, we describe an in silico approach to finding
 FDA-approved drugs that can be used by pharmacological repositioning as
 iALK. We used homology modelling to obtain a structural model of cdALK+
 protein and then performed molecular docking and molecular dynamics of the
 complex cdALK+-iALKs to generate the pharmacophore model. The
 pharmacophore was used to identify potential iALKs from FDA-approved drugs
 library by ligand-based virtual screening. Four pharmacophores with
 different atomistic characteristics were generated, resulting in six drugs
 that satisfied the proposed atomistic positions and coupled at the
 ATP-binding site. Mitoxantrone, riboflavin and abacavir exhibit the best
 interaction energies with 228.29, 165.40 and 133.48 kjoul/mol
 respectively. In addition, the special literature proposed these drugs for
 other types of diseases due to pharmacological repositioning. This study
 proposes FDA-approved drugs with ALK inhibitory characteristics. Moreover,
 we identified pharmacophores sites that can be tested with other
 pharmacological libraries.
description: Was used YASARA™ software to perform the simulations between the interactions of the cdALK+ with ATP and its known inhibitors: crizotinib, ceritinib, brigatinib, alectinib, lorlatinib.  The force fields used in the molecular dynamics, was AMBER14.  
description: # Molecular Dynamics DataSet for pharmacological repositioning in the
 treatment of non-small-cell lung cancer. 1/dryad.ttdz08m4m&gt; The
 presented database comprises files in ".tab" format, containing
 information pertaining to the molecular dynamics of the complex formed by
 the catalytic domain of ALK with the drugs under study. YASARA software
 was utilized for data acquisition, employing the AMBER 14 force field for
 molecular dynamics. A periodic cubic box, extending 20 Å around the
 complex, was generated. Physiological pH configurations at 7.4 and 0.9%
 NaCl for ion concentration as a mass fraction were applied.The system
 simulation was neutralized with TIP3P water molecules as a solvent,
 maintaining a density of 0.997 g/l. The simulation parameters included a
 temperature of 298 K, a pressure of 1 atm, and coulomb electrostatics with
 a cutoff of 8 Å, the default used by AMBER. The simulation time step was
 set at 2 ft, with each trajectory saved at 100 ps intervals. Subsequently,
 analysis was conducted using the YASARA™ macro (md_analyze_dynamics.mcr),
 assessing root mean square deviation (RMSD), root mean square fluctuation
 (RMSF), radius of gyration (Rg), and interaction bonds to identify key
 amino acids throughout the molecular dynamics, thus generating the
 pharmacophore. Molecular Dynamics (MD) results were obtained over 150 ns,
 measuring RMSD of the Cα, Radius of gyrations, RMSDLigMove, and
 RMSDLigConf for the ALK complexes with ATP, ABA, ALE, BRI, CER, CRI, LOR,
 MTX, and RIB. ## Description of the data and file structure The data is
 organized to facilitate users in extracting information from molecular
 dynamics for performing analyses such as RMSD, RMSF, Rg, bond
 interactions, and more. Each result is presented in columns within files
 stored in ".tab" format, enabling utilization and analysis in
 software such as R, Excel, or any other preferred tool. Each column is
 represented by a name, which are listed below with a brief description
 (This information is taken from YASARA): * *Time[ps]*: Displays the time
 in picoseconds of the molecular dynamics. * *Time[ns]*: Displays the time
 in nanoseconds of the molecular dynamics. **Analyses outside the
 simulation cell** * *CellLengthX, CellLengthY and CellLengthZ*: It defines
 the size of the cell around the atoms and how far the cell extends beyond
 the atoms. * *TotalEnergy*: These are the values of the potential energy
 of the system in Kj/mol, according to the force fields used. * *Bond,
 angle, dihedral, planarity, coulomb and vdw*: The following individual
 components of the total potential energy are plotted: bond energies
 [Bond], bond angle energies [Angle], dihedral angle energies [Dihedral],
 planarity or improper dihedral energies [Planarity], electrostatic
 energies [Coulomb] and Van der Waals energies [VdW]. Force field energies
 help to judge the structural quality of a protein. * *SurfVdW*: Van der
 Waals surface. * *SurfMol*: Molecular surface. * *SurfAcc*: Solvent
 accesible surface. * *SoluteHBonds*: The number of hydrogen bonds inside
 the solute. * *SltSlvHBonds*: Number of hydrogen bonds between solute and
 solvent. * *SelHBonds*: Internal hydrogen bonds. * *RecHBonds*: Hydrogen
 bonds with the rest of the solute. * *SlvHBonds*: Hydrogen bonds with
 water, including membrane molecules if any. * *TotHBonds*: The sum of
 SelHBonds, RecHBonds and SlvHBonds. * *Helix, sheet, turn, coil, helix310
 and helixPi*: The total percentages of alpha helices, beta sheets, turns,
 coils, 3-10 helices and pi helices are calculated. For clarification, a
 turn is simply a stretch of four residues that are not part of other
 secondary structure elements and form a hydrogen bond between the O of the
 first and the NH of the last residue. A coil is anything that does not fit
 into the other categories. Note that pi-helices [helices with hydrogen
 bonds between residues N and N+5] are rather unstable and thus do not
 normally occur in proteins, except for short bulges in alpha helices
 [which are often the result of single residue insertions and prolines].
 **Analyses outside the simulation cell** * *RadGyration*: Indicates the
 mean-square mass-weighted root range of a set of atoms that shared the
 mass centre. * *RMSDCa, RMSDBb and RMSDAll*: The Root Mean Square
 Deviation provides a measure of the average difference in distance between
 atoms within two or more molecules. RMSDCa refers to alpha carbon, RMSDBb
 refers to backbone and RMSDall refers to all atoms. * *RMSDLigMove*:
 Ligand movement RMSD (calculated after superposing the receptor). *
 *RMSDLigConf*: Ligand internal conformation RMSD (calculated after
 superposing the ligand). * *RMSF*: The Root Mean Square Fluctuation [RMSF]
 per solute residue is calculated from the average RMSF of its constituting
 atoms. **The molecular dynamics analysis files are listed below:** *
 *ALK_analysis*: Presents MD results for the catalytic domain of ALK
 without drug interaction. * *ALK_ATP_analysis*: Presents MD results for
 the catalytic domain of ALK interacting with ATP. * *ALK_ABA_analysis*:
 Presents MD results for the catalytic domain of ALK interacting with
 Abacavir. * *ALK_ALE_analysis*: Presents MD results for the catalytic
 domain of ALK interacting with Alectinib. * *ALK_BRI_analysis*: Presents
 MD results for the catalytic domain of ALK interacting with Brigatinib. *
 *ALK_CER_analysis*: Presents MD results for the catalytic domain of ALK
 interacting with Ceritinib. * *ALK_CRZ_analysis*: Presents MD results for
 the catalytic domain of ALK interacting with Crizotinib. *
 *ALK_LOR_analysis*: Presents MD results for the catalytic domain of ALK
 interacting with Lorlatinib. * *ALK_MTX_analysis*: Presents MD results for
 the catalytic domain of ALK interacting with Mitoxantrone. *
 *ALK_RIB_analysis*: Presents MD results for the catalytic domain of ALK
 interacting with Riboflavin. * *The RMSF files (.csv)*: Despict the
 movement of ALK residues along the molecular dynamics during interactions
 with the drugs. ## Sharing/Access information The molecular dynamics
 simulations have not been uploaded due to their size; however, they can be
 obtained by sending a request to .