Improving Blind Docking in DOCK6 through an Automated Preliminary Fragment Probing Strategy

Abstract

Probing protein surfaces to accurately predict the binding site and conformation of a small molecule is a challenge currently addressed through mainly two different approaches: blind docking and cavity detection-guided docking. Although cavity detection-guided blind docking has yielded high success rates, it is less practical when a large number of molecules must be screened against many detected binding sites. On the other hand, blind docking allows for simultaneous search of the whole protein surface, which however entails the loss of accuracy and speed. To bridge this gap, in this study, we developed and tested BLinDPyPr, an automated pipeline which uses FTMap and DOCK6 to perform a hybrid blind docking strategy. Through our algorithm, FTMap docked probe clusters are converted into DOCK6 spheres for determining binding regions. Because these spheres are solely derived from FTMap probes, their locations are contained in and specific to multiple potential binding pockets, which become the regions that are simultaneously probed and chosen by the search algorithm based on the properties of each candidate ligand. This method yields pose prediction results (45.2–54.3% success rates) comparable to those of site-specific docking with the classic DOCK6 workflow (49.7–54.3%) and is half as time-consuming as the conventional blind docking method with DOCK6.

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

“…Graziano reported that the non-intrinsic volumetric contribution at infinite dilution in water for mixture of hard spheres is always a small and positive quantity ( Graziano, 2006 ). We have recently confirmed this for model globular proteins ( Awoonor-Williams and Abu-Saleh, 2021 , Jofily et al, 2021 ). This is because this contribution to is the result of a balance between the repulsive volumetric component and the attractive component [see Eq.…”

“…The interaction from the specific and non-specific van der Waals forces of water as a solvent with the polar, non-polar and charged surface residues of the protein is quantified in the attractive volumetric contribution (see (14) , (16) ) to the partial or apparent molar volume . This volumetric quantity therefore is a measure of the contraction of the volume of water as a solvent in the proximity of the charged, and polar groups of the protein ( Ball, 2017 , Fleming and Fleming, 2018 , Jofily et al, 2021 , Kaur et al, 2021 ). Hence its importance to evaluate the induced changes in protein hydration due to ligand binding.…”

“…The partial molar volume of protein by definition ( Awoonor-Williams and Abu-Saleh, 2021 , Azam et al, 2021 , Fornés, 2008 , González-Paz et al, 2022 , Jofily et al, 2021 ) is considered to be constituted of two volumetric contributions, a molecular or geometric contribution (volume of van der Waals and volume of internal voids ) and a non-intrinsic contribution (volumetric contribution from repulsive and attractive interactions ): is the van der Waals volumes of all the protein constitutive atoms of protein and is volume of cavities within the protein from imperfect atomic packing, dependent of temperature, proportional to molar mass , and equal to the geometric volume of protein impenetrable to surrounding solvent molecules ( Azam et al, 2021 , Azam et al, 2020 , Ball, 2017 , Barletta and Fernández-Alberti, 2018 , Barletta et al, 2019 , Brovchenko et al, 2010 , Fleming and Fleming, 2018 , González-Paz et al, 2021 ). While the thermal volume (by definition is a quantity positive, i,e, ) is the empty volume around of protein which is due to the mutual protein-solvent vibrations, intermolec...…”

Interference of Polydatin/Resveratrol in the ACE2:Spike Recognition during COVID-19 Infection. A Focus on Their Potential Mechanism of Action through Computational and Biochemical Assays

“…A classical docking validation through re-docking an experimental ligand-protein complex cannot be therefore carried out in this case. In contrast to a "focused" docking targeted to an already known binding site, our docking calculations can be considered as "blind" docking [69][70][71][72][73][74].…”

Pharmacophore-Aided Virtual Screening and Molecular Dynamics Simulation Identifies TrkB Agonists for Treatment of CDKL5-Deficiency Disorders

“…Blind docking is an approach used to determine ligand binding sites and best ligand conformation in ligand-receptor interactions. 29 This technique is well suited for small protein targets and single ligand docking. It permits screening of the total area of the query protein to identify best residues with strongest interaction and best ligand conformation.…”