Chalcogen and Pnicogen Bonds in Complexes of Neutral Icosahedral and Bicapped Square-Antiprismatic Heteroboranes

A systematic quantum mechanical study of σ-hole (chalcogen, pnicogen, and halogen) bonding in neutral experimentally known <i>closo</i>-heteroboranes is performed. Chalcogens and pnicogens are incorporated in the borane cage, whereas halogens are considered as <i>exo</i>-substituents of dicarbaboranes. The chalcogen and pnicogen atoms in the heteroborane cages have partial positive charge and thus more positive σ-holes. Consequently, these heteroboranes form very strong chalcogen and pnicogen bonds. Halogen atoms in dicarbaboranes also have a highly positive σ-hole, but only in the case of C-bonded halogen atoms. In such cases, the halogen bond of heteroboranes is also strong and comparable to halogen bonds in organic compounds with several electron-withdrawing groups being close to the halogen atom involved in the halogen bond

Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water–octanol transfer free energies (Δ<i>G</i>_ow) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated Δ<i>G</i>_ow was observed in the following order: GB1 ∼ PB < GB7 ≪ MST < SMD ∼ COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of Δ<i>G</i>_ow for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications

Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water–octanol transfer free energies (Δ<i>G</i>_ow) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated Δ<i>G</i>_ow was observed in the following order: GB1 ∼ PB < GB7 ≪ MST < SMD ∼ COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of Δ<i>G</i>_ow for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications

SQM/COSMO Scoring Function at the DFTB3-D3H4 Level: Unique Identification of Native Protein–Ligand Poses

We have recently introduced the “SQM/COSMO” scoring function which combines a semiempirical quantum mechanical description of noncovalent interactions at the PM6-D3H4X level and the COSMO implicit model of solvation. This approach outperformed standard scoring functions but faced challenges with a metalloprotein featuring a Zn²⁺···S^– interaction. Here, we invoke SCC-DFTB3-D3H4, a higher-level SQM method, and observe improved behavior for the metalloprotein and high-quality results for the other systems. This method holds promise for diverse protein–ligand complexes including metalloproteins

Superior Performance of the SQM/COSMO Scoring Functions in Native Pose Recognition of Diverse Protein–Ligand Complexes in Cognate Docking

General and reliable description of structures and energetics in protein–ligand (PL) binding using the docking/scoring methodology has until now been elusive. We address this urgent deficiency of scoring functions (SFs) by the systematic development of corrected semiempirical quantum mechanical (SQM) methods, which correctly describe all types of noncovalent interactions and are fast enough to treat systems of thousands of atoms. Two most accurate SQM methods, PM6-D3H4X and SCC-DFTB3-D3H4X, are coupled with the conductor-like screening model (COSMO) implicit solvation model in so-called “SQM/COSMO” SFs and have shown unique recognition of native ligand poses in cognate docking in four challenging PL systems, including metalloprotein. Here, we apply the two SQM/COSMO SFs to 17 diverse PL complexes and compare their performance with four widely used classical SFs (Glide XP, AutoDock4, AutoDock Vina, and UCSF Dock). We observe superior performance of the SQM/COSMO SFs and identify challenging systems. This method, due to its generality, comparability across the chemical space, and lack of need for any system-specific parameters, gives promise of becoming, after comprehensive large-scale testing in the near future, a useful computational tool in structure-based drug design and serving as a reference method for the development of other SFs

QM/MM Calculations Reveal the Different Nature of the Interaction of Two Carborane-Based Sulfamide Inhibitors of Human Carbonic Anhydrase II

The crystal structures of two novel carborane-sulfamide inhibitors in the complex with human carbonic anhydrase II (hCAII) have been studied using QM/MM calculations. Even though both complexes possess the strongly interacting sulfamide···zinc ion motif, the calculations have revealed the different nature of binding of the carborane parts of the inhibitors. The neutral <i>closo</i>-carborane cage was bound to hCAII mainly via dispersion interactions and formed only very weak dihydrogen bonds. On the contrary, the monoanionic <i>nido</i> cage interacted with the protein mainly via electrostatic interactions. It formed short and strong dihydrogen bonds (stabilization of up to 4.2 kcal/mol; H···H distances of 1.7 Å) with the polar hydrogen of protein NH₂ groups. This type of binding is unique among all of the classical organic and inorganic inhibitors of hCAII. Virtual glycine scanning allowed us to identify the amino-acid side chains, which made important contributions to ligand-binding energies. In summary, using QM/MM calculations, we have provided a detailed understanding of the differences between the interactions of two carborane sulfamides, identified the amino acids of hCAII with which they interact, and thus paved the way for the computer-aided rational design of selective boron-cluster-containing hCAII inhibitors

Quantum Mechanics-Based Scoring Rationalizes the Irreversible Inactivation of Parasitic <i>Schistosoma mansoni</i> Cysteine Peptidase by Vinyl Sulfone Inhibitors

The quantum mechanics (QM)-based scoring function that we previously developed for the description of noncovalent binding in protein–ligand complexes has been modified and extended to treat covalent binding of inhibitory ligands. The enhancements are (i) the description of the covalent bond breakage and formation using hybrid QM/semiempirical QM (QM/SQM) restrained optimizations and (ii) the addition of the new Δ<i>G</i>_cov′ term to the noncovalent score, describing the “free” energy difference between the covalent and noncovalent complexes. This enhanced QM-based scoring function is applied to a series of 20 vinyl sulfone-based inhibitory compounds inactivating the cysteine peptidase cathepsin B1 of the Schistosoma mansoni parasite (SmCB1). The available X-ray structure of the SmCB1 in complex with a potent vinyl sulfone inhibitor K11017 is used as a template to build the other covalently bound complexes and to model the derived noncovalent complexes. We present the correlation of the covalent score and its constituents with the experimental binding data. Four outliers are identified. They contain bulky R₁′ substituents structurally divergent from the template, which might induce larger protein rearrangements than could be accurately modeled. In summary, we propose a new computational approach and an optimal protocol for the rapid evaluation and prospective design of covalent inhibitors with a conserved binding mode

Discovery of <i>N</i>²‑(4-Amino-cyclohexyl)-9-cyclopentyl‑<i>N</i>⁶‑(4-morpholin-4-ylmethyl-phenyl)-<i>9H</i>-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations

FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound <b>7d</b> displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with <b>7d</b> suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of <b>7d</b> in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib

Inorganic Polyhedral Metallacarborane Inhibitors of HIV Protease: A New Approach to Overcoming Antiviral Resistance

HIV protease (PR) is a prime target for rational anti-HIV drug design. We have previously identified icosahedral metallacarboranes as a novel class of nonpeptidic protease inhibitors. Now we show that substituted metallacarboranes are potent and specific competitive inhibitors of drug-resistant HIV PRs prepared either by site-directed mutagenesis or cloned from HIV-positive patients. Molecular modeling explains the inhibition profile of metallacarboranes by their unconventional binding mode

Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold

HIV protease is a primary target for the design of virostatics. Screening of libraries of non-peptide low molecular weight compounds led to the identification of several new compounds that inhibit HIV PR in the low micromolar range. X-ray structure of the complex of one of them, a dibenzo­[<i>b</i>,<i>e</i>]­[1,4]­diazepinone derivative, showed that two molecules of the inhibitor bind to the PR active site. Covalent linkage of two molecules of such a compound by a two-carbon linker led to a decrease of the inhibition constant of the resulting compound by 3 orders of magnitude. Molecular modeling shows that these dimeric inhibitors form two crucial hydrogen bonds to the catalytic aspartates that are responsible for their improved activity compared to the monomeric parental building blocks. Dibenzo­[<i>b</i>,<i>e</i>]­[1,4]­diazepinone analogues might represent a potential new class of HIV PIs