SQM/COSMO Scoring Function at the DFTB3-D3H4 Level: Unique Identification of Native Protein–Ligand Poses

Pecina, Adam; Haldar, Susanta; Fanfrlík, Jindřich; Meier, René; Řezáč, Jan; Lepšı́k, Martin; Hobza, Pavel

doi:10.1021/acs.jcim.6b00513

Cited by 42 publications

(61 citation statements)

References 66 publications

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“…The SQM/COSMO scoring function consists of two terms. The first term is an interaction energy in the gas phase calculated with the self‐consistent charge density functional tight‐binding scheme, including the third‐order terms and the 3OB Slater‐Koster parameters, augmented with the dispersion, hydrogen‐bonding and halogen bonding corrections (SCC‐DFTB3‐D3H4X) . The second term is the desolvation free energy change upon binding, evaluated at the COSMO level from the PM6/COSMO calculation using MOPAC with default parameters .…”

Section: Computational Sectionmentioning

confidence: 99%

“…The time requirements were thus reduced from days to tens of minutes, which makes the SQM/COSMO SF applicable to drug design even in an industrial context. It was demonstrated that the SQM/COSMO SF outperformed standard SFs at the PM6‐D3H4X and DFTB3‐D3H4X (for Zinc metalloproteins) levels in identifying the native binding pose, which is a critical prerequisite for affinity estimation in physics‐based scoring . However, it was not clear whether the simplified SQM/COSMO SF could reliably estimate P‐L binding affinities and provide the valuable ranking for an inhibitor series.…”

Section: Introductionmentioning

confidence: 99%

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Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes

et al. 2018

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Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (K ) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R of 0.56-0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications.

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Section: Computational Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes

et al. 2018

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“…The performance of DFTB3 is most impressive for structural properties of metal compounds, while the energetics are less accurate, especially for highly charged ligands, due presumably to the limited description of polarization and charge-transfer effects. Even with the current set of parameters, nevertheless, DFTB models have been shown to be highly effective for the description of ligand binding to zinc-enzymes (Pecina et al, 2017); systematic improvement of DFTB models for more complex transition-metal ions remains a topic of major interest.…”

Section: Background On Computational Methodsmentioning

confidence: 99%

Analysis of Phosphoryl-Transfer Enzymes with QM/MM Free Energy Simulations

Roston

Dong

Demapan

et al. 2018

Methods in Enzymology

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We discuss the application of quantum mechanics/molecular mechanics (QM/MM) free energy simulations to the analysis of phosphoryl transfers catalyzed by two enzymes: alkaline phosphatase and myosin. We focus on the nature of the transition state and the issue of mechanochemical coupling, respectively, in the two enzymes. The results illustrate unique insights that emerged from the QM/MM simulations, especially concerning the interpretation of experimental data regarding the nature of enzymatic transition states and coupling between global structural transition and catalysis in the active site. We also highlight a number of technical issues worthy of attention when applying QM/MM free energy simulations, and comment on a number of technical and mechanistic issues that require further studies.

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“…With corrections for London dispersion and hydrogen bonds, it is possible to achieve accuracy better than 1 kcal/mol in a wide range of noncovalent complexes of organic molecules . The resulting methods have also been successfully applied to large systems, such as to calculations of protein–ligand interactions in computer‐aided drug design . The issues encountered in dispersion and H‐bonds have been thoroughly studied, and while the present corrections are still not perfect, the current knowledge could be used for designing a new generation of more accurate SQM methods.…”

Section: Introductionmentioning

confidence: 99%

Description of halogen bonding in semiempirical quantum‐mechanical and self‐consistent charge density‐functional tight‐binding methods

Řezáč

2019

J Comput Chem

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This article analyzes the ability of semiempirical quantum‐mechanical methods (PM6 and PM7) and self‐consistent charge density‐functional tight‐binding (SCC‐DFTB) method DFTB3 to describe halogen bonds. Calculations of the electrostatic potential on the surface of molecules containing halogens show that the σ‐hole could be described well in modified neglect of diatomic overlap‐based methods. The situation is more complex in the case of DFTB3 where a simpler model is used for the electrostatics, but short‐ranged effects are covered in the Hamiltonian. All these methods can thus capture the effects that, for example, define the geometry of halogen bonds. The interaction energies are, however, affected by generally underestimated repulsion, which has been addressed earlier by standalone empirical corrections. Another approach to correcting this issue in DFTB3 is presented here—a modification of the energies of d‐orbitals on halogens yields better results than the empirical correction in DFTB3‐D3X, although it remains difficult to describe halogen and hydrogen bonds simultaneously. © 2019 Wiley Periodicals, Inc.

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SQM/COSMO Scoring Function at the DFTB3-D3H4 Level: Unique Identification of Native Protein–Ligand Poses

Cited by 42 publications

References 66 publications

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes

Analysis of Phosphoryl-Transfer Enzymes with QM/MM Free Energy Simulations

Description of halogen bonding in semiempirical quantum‐mechanical and self‐consistent charge density‐functional tight‐binding methods

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