Accuracy Assessment and Automation of Free Energy Calculations for Drug Design

As the free energy of binding of a ligand to its target is one of the crucial optimization parameters in drug design, its accurate prediction is highly desirable. In the present study we have assessed the average accuracy of free energy calculations for a total of 92 ligands binding to five different targets. To make this study and future larger scale applications possible we automated the setup procedure. Starting from user defined binding modes, the procedure decides which ligands to connect via a perturbation based on maximum common substructure criteria and produces all necessary parameter files for free energy calculations in AMBER 11. For the systems investigated, errors due to insufficient sampling were found to be substantial in some cases whereas differences in estimators (thermodynamic integration (TI) versus multistate Bennett acceptance ratio (MBAR)) were found to be negligible. Analytical uncertainty estimates calculated from a single free energy calculation were found to be much smaller than the sample standard deviation obtained from two independent free energy calculations. Agreement with experiment was found to be system dependent ranging from excellent to mediocre (RMSE = [0.9, 8.2, 4.7, 5.7, 8.7] kJ/mol). When restricting analyses to free energy calculations with sample standard deviations below 1 kJ/mol agreement with experiment improved (RMSE = [0.8, 6.9, 1.8, 3.9, 5.6] kJ/mol)

Highly Efficient Large Bite Angle Diphosphine Substituted Molybdenum Catalyst for Hydrosilylation

Treatment of the complex Mo­(NO)­Cl₃(NCMe)₂ with the large bite angle diphosphine, 2,2′-bis­(di­phenyl­phos­phino)­diphenylether (DPEphos) afforded the dinuclear species [Mo­(NO)­(P∩P)­Cl₂]₂[μCl]₂ (P∩P = DPEphos = (Ph₂PC₆H₄)₂O (<b>1</b>). <b>1</b> could be reduced in the presence of Zn and MeCN to the cationic complex [Mo­(NO)­(P∩P)­(NCMe)₃]⁺[Zn₂Cl₆]^2–_1/2 (<b>2</b>). In a metathetical reaction the [Zn₂Cl₆]^2–_1/2 counteranion was replaced with NaBAr^F₄ (BAr^F₄ = [B­{3,5-(CF₃)₂C₆H₃}₄]) to obtain the [BAr^F₄]⁻ salt [Mo­(NO)­(P∩P)­(NCMe)₃]⁺[BAr^F₄]⁻ (<b>3</b>). <b>3</b> was found to catalyze hydrosilylations of various <i>para</i> substituted benzaldehydes, cyclohexanecarboxaldehyde, 2-thiophenecarboxaldehyde, and 2-furfural at 120 °C. A screening of silanes revealed primary and secondary aromatic silanes to be most effective in the catalytic hydrosilylation with <b>3</b>. Also ketones could be hydrosilylated at room temperature using <b>3</b> and PhMeSiH₂. A maximum turnover frequency (TOF) of 3.2 × 10⁴ h^–1 at 120 °C and a TOF of 4400 h^–1 was obtained at room temperature for the hydrosilylation of 4-methoxyacetophenone using PhMeSiH₂ in the presence of <b>3</b>. Kinetic studies revealed the reaction rate to be first order with respect to the catalyst and silane concentrations and zero order with respect to the substrate concentrations. A Hammett study for various <i>para</i> substituted acetophenones showed linear correlations with negative ρ values of −1.14 at 120 °C and −3.18 at room temperature

Catalytic CO₂ Activation Assisted by Rhenium Hydride/B(C₆F₅)₃ Frustrated Lewis PairsMetal Hydrides Functioning as FLP Bases

Reaction of <b>1</b> with B­(C₆F₅)₃ under 1 bar of CO₂ led to the instantaneous formation of the frustrated Lewis pair (FLP)-type species [ReHBr­(NO)­(PR₃)₂(η²-OCO–B­(C₆F₅)₃)] (<b>2</b>, R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>) possessing two <i>cis</i>-phosphines and O_CO₂-coordinated B­(C₆F₅)₃ groups as verified by NMR spectroscopy and supported by DFT calculations. The attachment of B­(C₆F₅)₃ in <b>2a</b>,<b>b</b> establishes cooperative CO₂ activation via the Re–H/B­(C₆F₅)₃ Lewis pair, with the Re–H bond playing the role of a Lewis base. The Re­(I) η¹-formato dimer [{Re­(μ-Br)­(NO)­(η¹-OCHO–B­(C₆F₅)₃)­(P<i>i</i>Pr₃)₂}₂] (<b>3a</b>) was generated from <b>2a</b> and represents the first example of a stable rhenium complex bearing two <i>cis</i>-aligned, sterically bulky P<i>i</i>Pr₃ ligands. Reaction of <b>3a</b> with H₂ cleaved the μ-Br bridges, producing the stable and fully characterized formato dihydrogen complex [ReBrH₂(NO)­(η¹-OCHO–B­(C₆F₅)₃)­(P<i>i</i>Pr₃)₂] (<b>4a</b>) bearing <i>trans</i>-phosphines. Stoichiometric CO₂ reduction of <b>4a</b> with Et₃SiH led to heterolytic splitting of H₂ along with formation of bis­(triethylsilyl)­acetal ((Et₃SiO)₂CH₂, <b>7</b>). Catalytic reduction of CO₂ with Et₃SiH was also accomplished with the catalysts <b>1a</b>,<b>b</b>/B­(C₆F₅)₃, <b>3a</b>, and <b>4a</b>, showing turnover frequencies (TOFs) between 4 and 9 h^–1. The stoichiometric reaction of <b>4a</b> with the sterically hindered base 2,2,6,6-tetramethylpiperidine (TMP) furnished H₂ ligand deprotonation. Hydrogenations of CO₂ using <b>1a</b>,<b>b</b>/B­(C₆F₅)₃, <b>3a</b>, and <b>4a</b> as catalysts gave in the presence of TMP TOFs of up to 7.5 h^–1, producing [TMPH]­[formate] (<b>11</b>). The influence of various bases (R₂NH, R = <i>i</i>Pr, Cy, SiMe₃, 2,4,6-tri-<i>tert</i>-butylpyridine, NEt₃, P<i>t</i>Bu₃) was studied in greater detail, pointing to two crucial factors of the CO₂ hydrogenations: the steric bulk and the basicity of the base

Economical and Accurate Protocol for Calculating Hydrogen-Bond-Acceptor Strengths

A series of density functional/basis set combinations and second-order Møller–Plesset calculations have been used to test their ability to reproduce the trends observed experimentally for the strengths of hydrogen-bond acceptors in order to identify computationally efficient techniques for routine use in the computational drug-design process. The effects of functionals, basis sets, counterpoise corrections, and constraints on the optimized geometries were tested and analyzed, and recommendations (M06-2X/cc-pVDZ and X3LYP/cc-pVDZ with single-point counterpoise corrections or X3LYP/aug-cc-pVDZ without counterpoise) were made for suitable moderately high-throughput techniques

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applying an energetic cutoff, followed by geometric clustering, we demonstrate the striking robustness and efficiency of the approach in identifying highly populated conformational states of cyclic peptides. The resulting structural and thermodynamic information is benchmarked against interproton distances from NMR experiments and conformational states identified by X-ray crystallography. Using three different model systems of varying size and flexibility, we show that the method reliably reproduces experimentally determined structural ensembles and is capable of identifying key conformational states that include the bioactive conformation. Thus, the described approach is a robust method to generate conformations of peptidic macrocycles and holds promise for structure-based drug design

The “Catalytic Nitrosyl Effect”: NO Bending Boosting the Efficiency of Rhenium Based Alkene Hydrogenations

Diiodo Re­(I) complexes [ReI₂(NO)­(PR₃)₂(L)] (<b>3</b>, L = H₂O; <b>4</b> , L = H₂; R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>) were prepared and found to exhibit in the presence of “hydrosilane/B­(C₆F₅)₃” co-catalytic systems excellent activities and longevities in the hydrogenation of terminal and internal alkenes. Comprehensive mechanistic studies showed an inverse kinetic isotope effect, fast H₂/D₂ scrambling and slow alkene isomerizations pointing to an Osborn type hydrogenation cycle with rate determining reductive elimination of the alkane. In the catalysts’ activation stage phosphonium borates [R₃PH]­[HB­(C₆F₅)₃] (<b>6</b>, R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>) are formed. VT ²⁹Si- and ¹⁵N NMR experiments, and dispersion corrected DFT calculations verified the following facts: (1) Coordination of the silylium cation to the O_NO atom facilitates nitrosyl bending; (2) The bent nitrosyl promotes the heterolytic cleavage of the H–H bond and protonation of a phosphine ligand; (3) H₂ adds in a bifunctional manner across the Re–N bond. Nitrosyl bending and phosphine loss help to create two vacant sites, thus triggering the high hydrogenation activities of the formed “superelectrophilic” rhenium centers

Efficient Lewis Acid Promoted Alkene Hydrogenations Using Dinitrosyl Rhenium(−I) Hydride Catalysts

Highly efficient alkene hydrogenations were developed using NO-functionalized hydrido dinitrosyl rhenium catalysts of the type [ReH­(PR₃)₂(NO)­(NO­(LA))]­[Z] (<b>2</b>, LA = B­(C₆F₅)₃; <b>3</b>, LA = [Et]⁺, Z = [B­(C₆F₅)₄]⁻; <b>4</b>, LA = [SiEt₃]⁺, Z = [HB­(C₆F₅)₃]⁻; R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>). Lewis acid attachment to the NO ligand was found to facilitate bending at the N_OLA atom and concomitantly to open up a vacant site at the rhenium center. According to DFT calculations, the ability to bend follows the order <b>4</b> > <b>3</b> > <b>2</b>, which did not match with the order of increasing hydrogenation activities: <b>3</b> > <b>4</b> > <b>2</b>. The main factor spoiling catalytic performance was catalyst deactivation by detachment of the LA group occurring during the catalytic reaction course, which was found to go along with the decrease in order of DFT-calculated strengths of the O_NO–LA bonds. LA detachment from the O_NO atom could at least partly be prevented by LA addition as cocatalysts, which led to an extraordinary boost of the hydrogenation activities. For instance the “<b>1</b>/hydrosilane/B­(C₆F₅)₃” (1:5:5) system exhibited the highest performance, with TOFs up to 1.2 × 10⁵ h^–1 (1-hexene, 1-octene, cyclooctene, cyclohexene). The cocatalyst [Et₃O]­[B­(C₆F₅)₄] showed the smallest effect, presumably due to the strong Lewis acidic character of the reagent causing side-reactions before reacting with <b>1a</b>,<b>b</b>. The catalytic reaction course crucially involves not only reversible bending at the N_OLA atom but also loss of a PR₃ ligand, forming 16<i>e</i> or 14<i>e</i> monohydride reactive intermediates, which drive an Osborn-type hydrogenation cycle with olefin before H₂ addition

Efficient Lewis Acid Promoted Alkene Hydrogenations Using Dinitrosyl Rhenium(−I) Hydride Catalysts

Highly efficient alkene hydrogenations were developed using NO-functionalized hydrido dinitrosyl rhenium catalysts of the type [ReH­(PR₃)₂(NO)­(NO­(LA))]­[Z] (<b>2</b>, LA = B­(C₆F₅)₃; <b>3</b>, LA = [Et]⁺, Z = [B­(C₆F₅)₄]⁻; <b>4</b>, LA = [SiEt₃]⁺, Z = [HB­(C₆F₅)₃]⁻; R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>). Lewis acid attachment to the NO ligand was found to facilitate bending at the N_OLA atom and concomitantly to open up a vacant site at the rhenium center. According to DFT calculations, the ability to bend follows the order <b>4</b> > <b>3</b> > <b>2</b>, which did not match with the order of increasing hydrogenation activities: <b>3</b> > <b>4</b> > <b>2</b>. The main factor spoiling catalytic performance was catalyst deactivation by detachment of the LA group occurring during the catalytic reaction course, which was found to go along with the decrease in order of DFT-calculated strengths of the O_NO–LA bonds. LA detachment from the O_NO atom could at least partly be prevented by LA addition as cocatalysts, which led to an extraordinary boost of the hydrogenation activities. For instance the “<b>1</b>/hydrosilane/B­(C₆F₅)₃” (1:5:5) system exhibited the highest performance, with TOFs up to 1.2 × 10⁵ h^–1 (1-hexene, 1-octene, cyclooctene, cyclohexene). The cocatalyst [Et₃O]­[B­(C₆F₅)₄] showed the smallest effect, presumably due to the strong Lewis acidic character of the reagent causing side-reactions before reacting with <b>1a</b>,<b>b</b>. The catalytic reaction course crucially involves not only reversible bending at the N_OLA atom but also loss of a PR₃ ligand, forming 16<i>e</i> or 14<i>e</i> monohydride reactive intermediates, which drive an Osborn-type hydrogenation cycle with olefin before H₂ addition

Efficient Lewis Acid Promoted Alkene Hydrogenations Using Dinitrosyl Rhenium(−I) Hydride Catalysts

Highly efficient alkene hydrogenations were developed using NO-functionalized hydrido dinitrosyl rhenium catalysts of the type [ReH­(PR₃)₂(NO)­(NO­(LA))]­[Z] (<b>2</b>, LA = B­(C₆F₅)₃; <b>3</b>, LA = [Et]⁺, Z = [B­(C₆F₅)₄]⁻; <b>4</b>, LA = [SiEt₃]⁺, Z = [HB­(C₆F₅)₃]⁻; R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>). Lewis acid attachment to the NO ligand was found to facilitate bending at the N_OLA atom and concomitantly to open up a vacant site at the rhenium center. According to DFT calculations, the ability to bend follows the order <b>4</b> > <b>3</b> > <b>2</b>, which did not match with the order of increasing hydrogenation activities: <b>3</b> > <b>4</b> > <b>2</b>. The main factor spoiling catalytic performance was catalyst deactivation by detachment of the LA group occurring during the catalytic reaction course, which was found to go along with the decrease in order of DFT-calculated strengths of the O_NO–LA bonds. LA detachment from the O_NO atom could at least partly be prevented by LA addition as cocatalysts, which led to an extraordinary boost of the hydrogenation activities. For instance the “<b>1</b>/hydrosilane/B­(C₆F₅)₃” (1:5:5) system exhibited the highest performance, with TOFs up to 1.2 × 10⁵ h^–1 (1-hexene, 1-octene, cyclooctene, cyclohexene). The cocatalyst [Et₃O]­[B­(C₆F₅)₄] showed the smallest effect, presumably due to the strong Lewis acidic character of the reagent causing side-reactions before reacting with <b>1a</b>,<b>b</b>. The catalytic reaction course crucially involves not only reversible bending at the N_OLA atom but also loss of a PR₃ ligand, forming 16<i>e</i> or 14<i>e</i> monohydride reactive intermediates, which drive an Osborn-type hydrogenation cycle with olefin before H₂ addition

Efficient Lewis Acid Promoted Alkene Hydrogenations Using Dinitrosyl Rhenium(−I) Hydride Catalysts

Highly efficient alkene hydrogenations were developed using NO-functionalized hydrido dinitrosyl rhenium catalysts of the type [ReH­(PR₃)₂(NO)­(NO­(LA))]­[Z] (<b>2</b>, LA = B­(C₆F₅)₃; <b>3</b>, LA = [Et]⁺, Z = [B­(C₆F₅)₄]⁻; <b>4</b>, LA = [SiEt₃]⁺, Z = [HB­(C₆F₅)₃]⁻; R = <i>i</i>Pr <b>a</b>, Cy <b>b</b>). Lewis acid attachment to the NO ligand was found to facilitate bending at the N_OLA atom and concomitantly to open up a vacant site at the rhenium center. According to DFT calculations, the ability to bend follows the order <b>4</b> > <b>3</b> > <b>2</b>, which did not match with the order of increasing hydrogenation activities: <b>3</b> > <b>4</b> > <b>2</b>. The main factor spoiling catalytic performance was catalyst deactivation by detachment of the LA group occurring during the catalytic reaction course, which was found to go along with the decrease in order of DFT-calculated strengths of the O_NO–LA bonds. LA detachment from the O_NO atom could at least partly be prevented by LA addition as cocatalysts, which led to an extraordinary boost of the hydrogenation activities. For instance the “<b>1</b>/hydrosilane/B­(C₆F₅)₃” (1:5:5) system exhibited the highest performance, with TOFs up to 1.2 × 10⁵ h^–1 (1-hexene, 1-octene, cyclooctene, cyclohexene). The cocatalyst [Et₃O]­[B­(C₆F₅)₄] showed the smallest effect, presumably due to the strong Lewis acidic character of the reagent causing side-reactions before reacting with <b>1a</b>,<b>b</b>. The catalytic reaction course crucially involves not only reversible bending at the N_OLA atom but also loss of a PR₃ ligand, forming 16<i>e</i> or 14<i>e</i> monohydride reactive intermediates, which drive an Osborn-type hydrogenation cycle with olefin before H₂ addition