Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations

Abstract

The lack of conformational sampling in virtual screening projects can lead to inefficient results because many of the potential drugs may not be able to bind to the target protein during the static docking simulations. Here, we performed ensemble docking for around 2000 United States Food and Drug Administration (FDA)-approved drugs with the RNA-dependent RNA polymerase (RdRp) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a target. The representative protein structures were generated by clustering classical molecular dynamics trajectories, which were evolved using three solvent scenarios, namely, pure water, benzene/water and phenol/water mixtures. The introduction of dynamic effects in the theoretical model showed improvement in docking results in terms of the number of strong binders and binding sites in the protein. Some of the discovered pockets were found only for the cosolvent simulations, where the nonpolar probes induced local conformational changes in the protein that lead to the opening of transient pockets. In addition, the selection of the ligands based on a combination of the binding free energy and binding free energy gap between the best two poses for each ligand provided more suitable binders than the selection of ligands based solely on one of the criteria. The application of cosolvent molecular dynamics to enhance the sampling of the configurational space is expected to improve the efficacy of virtual screening campaigns of future drug discovery projects.

CosolvKit: a versatile tool for cosolvent MD preparation and analysis

“…The default solvent used is water, but the user can specify any solvent by providing its SMILES strings. During the simulation, interactions between aromatic or other highly lipophilic molecules can induce hydrophobic effects that result in aggregates in aqueous solutions 4,20 . The https://doi.org/10.26434/chemrxiv-2024-rmsnj ORCID: https://orcid.org/0000-0003-0223-3214 Content not peer-reviewed by ChemRxiv.…”

An Exploration of Small Molecules That Bind Human Single-Stranded DNA Binding Protein 1

“…Cosolvent MD simulations were performed to better understand the binding of the six compounds to hSSB1. This approach considers protein flexibility and allosteric binding, opening pockets that are not available in the apo form [37]. For each compound, we completed five MD replicas of 300 ns.…”

Exploring Aromatic Cage Flexibility Using Cosolvent Molecular Dynamics Simulations─An In-Silico Case Study of Tudor Domains

“…Conformational changes upon ligand binding (induced fit) can hamper the accurate binding mode prediction using classical docking studies . Classical MD simulations and clustering can be performed to better predict the binding mode, however using pure water as solvent can only yield restricted insight since the chemical properties of ligands are not taken into consideration . In this study, we wanted to investigate whether the use of cosolvent MDs can not only help recognize the hotspots, but also sample the binding site conformations, specifically binding sites comprising aromatic cages.…”

“… 27 Classical MD simulations and clustering can be performed to better predict the binding mode, however using pure water as solvent can only yield restricted insight since the chemical properties of ligands are not taken into consideration. 28 In this study, we wanted to investigate whether the use of cosolvent MDs can not only help recognize the hotspots, but also sample the binding site conformations, specifically binding sites comprising aromatic cages. In this work, we focused on two Tudor domain containing proteins namely Spindlin 1 (SPIN1) and survival motor neuron protein (SMN).…”