Computational protocol: Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

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[…] Two datasets were generated. The first one includes 141 enantiomeric pairs with activities against some selected molecular targets. The second one includes 202 pairs with small differences in MW with activities against the same molecular targets. The selected compounds have biological activities against the molecular targets AChE, BChE, MAO-A, MAO-B, ACE, NEP, and ECE [,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,]. All the studied ligands in this work were sketched using Maestro Suite and prepared using LigPrep with the force field OPLS_2005 []. The biological activities were converted to logarithmic scale for comparison with calculated binding energies.The structural files of the following protein targets were downloaded from the RCSB Protein Data Bank repository: human AChE (hAChE) PDB ID: 4M0E []; mus musculus AChE (mAChE) PDB ID: 2HA2 []; human BChE (hBChE) PDB ID: 1POI []; human MAO-A (hMAO-A) PDB ID: 2BXR []; rattus norvegicus MAO-A (mMAO-A) PDB ID: 1O5W []; human MAO-B (hMAO-B) PDB ID: 1S3E []; human ACE (hACE) PDB ID: 1O86 []; human NEP (hNEP) PDB ID: 2QPJ []; and human ECE (hECE) PDB ID: 3DWB []. All targets were processed with the Protein Preparation Wizard in the Schrödinger Suite []. Hydrogen atoms were added followed by the adjustment of bond orders. The protonation and tautomeric states for protonable residues were adjusted to match pH = 7.4. Missing residues and loop segments near the active site were added by using Prime []. Water molecules beyond 5.0 Å from the active site were deleted. Proteins were finally subjected to geometry optimization by using OPLS_2005 force field []. [...] Docking tests were performed using the software Glide [] and Autodock Vina []. Glide offers a complete solution for ligand–receptor docking and is widely used for drug discovery [,], virtual screening [,], structure-activity relationship analysis [,,], pharmacophore modeling [,,], evaluation of enzymatic reaction pathways [,], and other studies. All grid boxes for molecular docking were centered in the ligand position coming from the crystal structures. The grid boxes’ dimensions were 35 × 35 × 35 Å in order to include all binding sites. High-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) Glide modes were proved.Default docking parameters were used. Glide docking uses hierarchical filters to find the best ligand binding locations in the defined receptor grid space. The filters include positional, conformational, and orientational sampling of the ligand and subsequent energy evaluation of the interactions between the ligand and the protein. Ligand minimization in the receptor field is carried out using the OPLS-AA force field [] with a distance-dependent dielectric of 2.0. Afterward, the lowest energy poses are subjected to a Monte Carlo (MC) procedure that samples the nearby torsional minima. The best pose for a given ligand is determined by the GlideScore score [], including terms for buried polar groups and steric clashes.Autodock Vina parameters were defined in a similar way as in Glide. Grid boxes dimensions were 35 × 35 × 35 Å. Autodock Vina implements an efficient scoring function optimization algorithm for estimating protein-ligand affinity and a search algorithm for predicting the plausible binding modes []. Vina repeats the calculations several times with different randomizations, it can be performed in parallel with a multicore machine. […]

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