Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition

Celis-Barros, Cristián; Saavedra-Rivas, Leslie; Salgado, J. Cristian; Cassels, Bruce K.; Zapata‐Torres, Gerald

doi:10.1007/s10822-014-9802-7

Cited by 18 publications

(20 citation statements)

References 36 publications

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“…Moreover, the C-I· · ·O angles ranged from 163 • to 176 • in almost all cases and only for the complex involving (P)-24 a lower value of 150 • was observed. It is worth noting that, in general, angles ranging from 160 • to 180 • are considered acceptable to decide if the interaction corresponds to a halogen bond [61]. In contrast, the X· · ·O C angles showed a wide distribution ranging from 97 • to 167 • with no clear trend related to the implication of XB.…”

Section: Molecular Dynamics (Mds)mentioning

confidence: 97%

Insights into halogen bond-driven enantioseparations

Peluso

Mamane

Aubert

et al. 2016

Journal of Chromatography A

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Section: Molecular Dynamics (Mds)mentioning

confidence: 97%

Insights into halogen bond-driven enantioseparations

Peluso

Mamane

Aubert

et al. 2016

Journal of Chromatography A

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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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“…This conformation is best explained by the non-covalent interactions established in the active site by p-CMP. Also, taking into account the anisotropic electronic distribution on the chlorine atom [ 45 ], the generation of a positive σ hole at the far end of the C-Cl bond allows a specific and orthogonal hydrogen bond to form. Specifically, a weak hydrogen bond can be seen between the chlorine atom of p-CMP and the amide moiety of Cys172 ( S5 Fig ).…”

Section: Resultsmentioning

confidence: 99%

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

et al. 2016

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Despite their structural and chemical commonalities, p-chloro-β-methylphenethylamine and p-methoxy-β-methylphenethylamine display distinct inhibitory and substrate activities upon MAO-B binding. Density Functional Theory (DFT) quantum chemical calculations reveal that β-methylation and para-substitution underpin the observed activities sustained by calculated transition state energy barriers, attained conformations and key differences in their interactions in the enzyme’s substrate binding site. Although both compounds meet substrate requirements, it is clear that β-methylation along with the physicochemical features of the para-substituents on the aromatic ring determine the activity of these compounds upon binding to the MAO B-isoform. While data for a larger set of compounds might lend generality to our conclusions, our experimental and theoretical results strongly suggest that the contrasting activities displayed depend on the conformations adopted by these compounds when they bind to the enzyme.

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Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition

Cited by 18 publications

References 36 publications

Insights into halogen bond-driven enantioseparations

Insights into halogen bond-driven enantioseparations

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

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

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