The SQM/COSMO filter: reliable native pose identification based on the quantum-mechanical description of protein–ligand interactions and implicit COSMO solvation

Current virtual screening tools are fast, but reliable scoring is elusive. Here, we present the "SQM/COSMO filter", a novel scoring function featuring a quantitative semiempirical quantum mechanical (SQM) description of all types of noncovalent interactions coupled with implicit COSMO solvation. We show unequivocally that it outperforms eight widely used scoring functions. The accuracy and chemical generality of the SQM/COSMO filter make it a perfect tool for late stages of virtual screening

Face-Fusion of Icosahedral Boron Hydride Increases Affinity to γ‐Cyclodextrin: closo,closo‐[B₂₁H₁₈]⁻ as an Anion with Very Low Free Energy of Dehydration

[Abstract] The supramolecular recognition of closo,closo‐[B₂₁H₁₈]⁻ by cyclodextrins (CDs) has been studied in aqueous solution by isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. These solution studies follow up on previous mass‐spectrometric measurements and computations, which indicated the formation and stability of CD ⋅ B₂₁H₁₈⁻ complexes in the gas phase. The thermodynamic signature of solution‐phase binding is exceptional, the association constant for the γ‐CD complex with B₂₁H₁₈⁻ reaches 1.8×10⁶ M⁻¹, which is on the same order of magnitude as the so far highest observed value for the complex between γ‐CD and a metallacarborane. The nature of the intermolecular interaction is also examined by quantum‐mechanical computational protocols. These suggest that the desolvation penalty, which is particularly low for the B₂₁H₁₈⁻ anion, is the decisive factor for its high binding strength. The results further suggest that the elliptical macropolyhedral boron hydride is another example of a CD binder, whose extraordinary binding affinity is driven by the chaotropic effect, which describes the intrinsic affinity of large polarizable and weakly solvated chaotropic anions to hydrophobic cavities and surfaces in aqueous solution.K.I.A. and W.M.N. are grateful to the DFG for grant NA-686/8 within the priority program SPP 1807 “Control of London Dispersion Interactions in Molecular Chemistry”. J.H., J.F., and D.H. thank the Czech Science Foundation (grant number 17-08045S) and M.I.F.P., M.C.L, and J.A.S.L. thank the regional government Xunta de Galicia for financial support (Project Grupo Potencial Crecemento -GPC- ED431B 2017/59). J.M.O.-E. acknowledges financial support from the Spanish MICINN through project CTQ2018-094644-B-C22German Research Foundation; NA‐686/8Czech Science Foundation; 17‐08045SXunta de Galicia; ED431B 2017/5

Nuclear magnetic shielding of monoboranes : calculation and assessment of 11B NMR chemical shifts in planar BX3 and in tetrahedral [BX4]- systems

The financial support of the Czech Science Foundation (project No. 17-08045S) is gratefully acknowledged.11B NMR chemical shifts of tricoordinated BX3 and tetracoordinated BX4- compounds (X = H, CH3, F, Cl, Br, I, OH, SH, NH2, and CH=CH2) were computed and the shielding tensors were explored not only within the nonrelativistic GIAO approach but also by applying both relativistic ZORA computations including spin-orbit coupling as well as by employing scalar nonrelativistic ZORA computations (BP86 level of density functional theory). The contributions of the spin-orbit coupling to the overall shieldings are decisive for X = Br and I in both series. No relationship was found between the 2p orbital occupancies or 1/∆E (difference between LUMO and suitably occupied MO that can be coupled with LUMO) with the shielding tensors (or their principal values) in the BX3 series. However, a multidimensional statistical approach known as factor analysis (frequently used in chemometrics) revealed that three factors account for 92 % of the cumulative proportion of total variance. The main components of the first factor are occupancies in the 2px and 2py orbitals and 1/∆E, the second factor is mainly the occupancy in the 2pz orbital and the inductive substituent parameters by Taft and, finally, the third factor consists exclusively (99.3 %) of the electrostatic potentials (Vmax), which is directly related to the so-called π-hole magnitudes.PostprintPeer reviewe

Binary twinned-icosahedral [B21H18]- interacts with cyclodextrins as a precedent for its complexation with other organic motifs

The weakly coordinating binary macropolyhedral anion closo,closo-[BH] (B21; D symmetry) has been synthesized using a simplified strategy compared to that in the literature. While gas-phase complexes of B21 with β- and γ-cyclodextrin (CD) were detected using ESI FT-ICR spectrometric measurements, α-CD did not bind to the B21 guest. This spectroscopic evidence has been interpreted using quantum-chemical computations, showing that β- and γ-CD are able to interact with B21 due to their larger cavities, in contrast to the smaller α-CD. The hydridic B-H vectors of the B21 anion interact with K counterions and, via dihydrogen bonding, also with the partially positively charged hydrogens of the CD sugar units in the modeled β- and γ-CD complexes. In summary, it has been shown by combined spectrometric/computational analysis that macropolyhedral boron hydride anions with two counterions can form stable complexes with β- and γ-CD in the gas phase, offering a new perspective for the future investigation of this remarkable anion in the areas of supramolecular and medicinal chemistries.Peer Reviewe

Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R(2) = 0.49). However, the addition of the active-site waters resulted in significant improvement (R(2) = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors

The Effect of Halogen-to-Hydrogen Bond Substitution on Human Aldose Reductase Inhibition

The effect of halogen-to-hydrogen bond substitution on the binding energetics and biological activity of a human aldose reductase inhibitor has been studied using X-ray crystallography, IC50 measurements, advanced binding free energy calculations, and simulations. The replacement of Br or I atoms by an amine (NH2) group has not induced changes in the original geometry of the complex, which made it possible to study the isolated features of selected noncovalent interactions in a biomolecular complex