2019
DOI: 10.1021/acs.jctc.9b00748
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Binding Thermodynamics of Host–Guest Systems with SMIRNOFF99Frosst 1.0.5 from the Open Force Field Initiative

Abstract: Designing ligands that bind their target biomolecules with high affinity and specificity is a key step in smallmolecule drug discovery, but accurately predicting protein-ligand binding free energies remains challenging. Key sources of errors in the calculations include inadequate sampling of conformational space, ambiguous protonation states, and errors in force fields. Noncovalent complexes between a host molecule with a binding cavity and a drug-like guest molecules have emerged as powerful model systems. As… Show more

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Cited by 32 publications
(58 citation statements)
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“…Previous studies on CDs ( -CD, -CD, and mono-3-carboxyproponamido-CD) report two distinct bound states for each hostguest pair. The first bound state, called the "primary orientation", has the guest polar group (i.e., alcohol, ammonium, carboxylate) towards the glucose subunits primary alcohols, while the "secondary orientation" has the guest polar group towards the secondary alcohol [76,77] (Figure 4). Though a possible third "surface orientation"/binding mode has been speculated to exist, it may be this is a transition needed for the guest to flip from primary to secondary phase orientation or vice-versa [43].…”
Section: Cyclodextrins (Cds) and Cyclodextrin Derivativesmentioning
confidence: 99%
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“…Previous studies on CDs ( -CD, -CD, and mono-3-carboxyproponamido-CD) report two distinct bound states for each hostguest pair. The first bound state, called the "primary orientation", has the guest polar group (i.e., alcohol, ammonium, carboxylate) towards the glucose subunits primary alcohols, while the "secondary orientation" has the guest polar group towards the secondary alcohol [76,77] (Figure 4). Though a possible third "surface orientation"/binding mode has been speculated to exist, it may be this is a transition needed for the guest to flip from primary to secondary phase orientation or vice-versa [43].…”
Section: Cyclodextrins (Cds) and Cyclodextrin Derivativesmentioning
confidence: 99%
“…Though a possible third "surface orientation"/binding mode has been speculated to exist, it may be this is a transition needed for the guest to flip from primary to secondary phase orientation or vice-versa [43]. The difference in binding free energy for the two main orientations has been reported as being about 2 kcal/mol and up to 5 kcal/mol using several different force fields [77], with this of course also depending on the guest. The same report suggested that using GAFF v2.1 better models the flexibility of -CD compared to the SMIRNOOFF99Frosst and GAFF v1.7 force fields also examined.…”
Section: Cyclodextrins (Cds) and Cyclodextrin Derivativesmentioning
confidence: 99%
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“…The types and numerical parameters of SMIRNOFF99Frosst were designed for maximal consistency with the Parm@Frosst force field [34], a general force field in the AMBER family with similarities to GAFF, and indeed, SMIRNOFF99Frosst retained the accuracy of simulations for several important properties, such as the densities and dielectric constants of organic liquids, hydration free energies of small molecules, and host-guest binding thermodynamics. [35] Importantly, the new typing formalism allowed this to be achieved with only ∼ 300 lines of parameters, which may be compared with > 6000 lines of parameters for GAFF. Moreover, the independent hierarchies of typing rules for each force field term allows for simple extensions to increase accuracy in new areas of chemical space.…”
Section: Introductionmentioning
confidence: 99%