Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor

Rana, Neha; Conley, Jason M.; Soto-Velasquez, Monica; León, Francisco; Cutler, Stephen J.; Watts, Val J.; Lill, Markus A.

doi:10.1021/acs.jcim.6b00454

Cited by 13 publications

(16 citation statements)

References 26 publications

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“…33,34,41,42 The EP-based strategy is becoming widely used in MD simulations of protein-ligand systems. [43][44][45][46] Some of these studies employed the MD trajectories in subsequent MM-PBSA 32,47 or MM-GBSA (Molecular Mechanics -Generalized-Born Surface Area) calculations [48][49][50][51] to estimate ∆G bind . Even though the MM/MD sampling is, in principle, more accurate in the presence of an EP, its impact on the accuracy of ∆G solv predictions is yet unknown.…”

Section: Introductionmentioning

confidence: 99%

Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Nunes¹,

Viçosa²,

Costa³

2019

Preprint

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<div>To model halogen bond phenomena using classical force fields, an extra-point (EP) of charge is frequently introduced at a given distance from the halogen (X) to emulate the σ-hole. The resulting molecular dynamics (MD) trajectories can be used in subsequent molecular mechanics (MM) combined with Poisson–Boltzmann and surface area calculations (MM PBSA) to estimate protein–ligand binding free energies (∆Gbind). While EP addition improves the MM/MD description of halogen-containing systems, its effect on the calculation of solvation free energies (∆Gsolv) using the PBSA approach is yet to be assessed. As the PBSA calculations depend, among other parameters, on the empirical assignment of radii (PB radii), a problematic issue arises since standard halogen radii are smaller than the typical X· · · EP distances (usually corresponding to Rmin), thus placing the EP within the solvent dielectric. Herein, we performed a comprehensive study on the performance of PBSA (using three different setups) in the calculation of ∆Gsolv values for 142 halogenated compounds (bearing Cl, Br, or I) for which the experimental values are known. By conducting an optimization (minimizing the error against experimental values), we provide a new optimized set of halogen PB radii, for each PBSA setup, that should be used when the EP is located at R min in the context of GAFF. A simultaneous optimization of PB radii and X· · · EP distances shows that a wide range of distance/radius pairs can be used without significant loss of accuracy, therefore laying the basis for expanding this halogen radii optimization strategy to other force fields and EP implementations. As ligand ∆Gsolv estimation is an important term in the determination of protein–ligand ∆Gbind , this work is particularly relevant in the framework of structure-based virtual screening and related computer-aided drug design routines.</div>

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Section: Introductionmentioning

confidence: 99%

Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Nunes¹,

Viçosa²,

Costa³

2019

Preprint

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Section: Introductionmentioning

confidence: 99%

Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Nunes

Vila-Viçosa

Costa

2019

J. Chem. Theory Comput.

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To model halogen bond phenomena using classical force fields, an extra-point (EP) of charge is frequently introduced at a given distance from the halogen (X) to emulate the σ-hole. The resulting molecular dynamics (MD) trajectories can be used in subsequent molecular mechanics (MM) combined with Poisson-Boltzmann and surface area calculations (MM PBSA) to estimate protein-ligand binding free energies (∆G bind). While EP addition improves the MM/MD description of halogen-containing systems, its effect on the calculation of solvation free energies (∆G solv) using the PBSA approach is yet to be assessed. As the PBSA calculations depend, among other parameters, on the empirical assignment of radii (PB radii), a problematic issue arises since standard halogen radii are smaller than the typical X• • • EP distances (usually corresponding to R min), thus placing the EP within the solvent dielectric. Herein, we performed a comprehensive study on the performance of PBSA (using three different setups) in the calculation of ∆Gsolv values for 142 halogenated compounds (bearing Cl, Br, or I) for which the experimental values are known. By conducting an optimization (minimizing the error against experimental values), we provide a new optimized set of halogen PB radii, for each PBSA setup, that should be used when the EP is located at R min in the context of GAFF. A simultaneous optimization of PB radii and X• • • EP distances shows that a wide range of distance/radius pairs can be used without significant loss of accuracy, therefore laying the basis for expanding this halogen radii optimization strategy to other force fields and EP implementations. As ligand ∆G solv estimation is an important term in the determination of protein-ligand ∆G bind , this work is particularly relevant in the framework of structure-based virtual screening and related computer-aided drug design routines. File list (2) download file view on ChemRxiv 2019-XB-PBSA-Vicosa-Nunes-Costa-v2.pdf (4.97 MiB) download file view on ChemRxiv 2019-XB-PBSA-Vicosa-Nunes-Costa-SI-v2.pdf (0.93 MiB)

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“…To explore the existence of phospholipid-halogen interactions, we carried out MM/MD simulations with a series of halobenzenes in a hydrated phospholipid (POPC) bilayer environment, using an extra-point (EP) approach to model the XB-properties of the halogenated species. [81][82][83][84] This methodology, that had been widely applied in the computational investigation of a variety of protein-ligand systems, [86][87][88][89]102,104,105 provided evidences supporting the role of XB interactions in lipid-ligand recognition events. Our results also showed that, similarly to other biological systems, 30,80 XBs In summary, the role of XB interactions in lipid-ligand systems was tackled for the first time and our data provide important insights into membrane-(halo)drug recognition mechanisms at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

Halogen Bonding: An Underestimated Player in Membrane–Ligand Interactions

2021

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Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein-ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from model phospholipid bilayers, thus supporting the existence of XB mediated phospholipid-halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in water-to membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggests that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models. File list (2) download file view on ChemRxiv 2021-XB-membranes-Nunes-Vicosa-Costa-ver3.pdf (5.43 MiB) download file view on ChemRxiv 2021-XB-membranes-Nunes-Vicosa-Costa-ver3-SI.pdf (10.30 MiB)

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Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor

Cited by 13 publications

References 26 publications

Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole

Halogen Bonding: An Underestimated Player in Membrane–Ligand Interactions

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