SQM/COSMO Scoring Function: Reliable Quantum-Mechanical Tool for Sampling and Ranking in Structure-Based Drug Design.

Invited for this month's cover is the group of Prof. Pavel Hobza, Czech Academy of Sciences, Prague. The cover picture shows a powerful automated quantum mechanics based SQM/COSMO approach to protein-ligand scoring. It comprises thorough preparation of ligand structures, extensive generation of binding complexes, fast geometry relaxation and reliable affinity prediction. Read the full text of the Minireview at 10.1002/cplu.202000120.

SQM/COSMO Scoring Function: Reliable Quantum-Mechanical Tool for Sampling and Ranking in Structure-Based Drug Design.

Quantum mechanical (QM) methods have been gaining importance in structure-based drug design where a reliable description of protein-ligand interactions is of utmost significance. However, strategies i. e. QM/MM, fragmentation or semiempirical (SQM) methods had to be pursued to overcome the unfavorable scaling of QM methods. Various SQM-based approaches have significantly contributed to the accuracy of docking and improvement of lead compounds. Parametrizations of SQM and implicit solvent methods in our laboratory have been instrumental to obtain a reliable SQM-based scoring function. The experience gained in its application for activity ranking of ligands binding to tens of protein targets resulted in setting up a faster SQM/COSMO scoring approach, which outperforms standard scoring methods in native pose identification for two dozen protein targets with ten thousand poses. Recently, SQM/COSMO was effectively applied in a proof-of-concept study of enrichment in virtual screening. Due to its superior performance, feasibility and chemical generality, we propose the SQM/COSMO approach as an efficient tool in structure-based drug design.

Impressive Enrichment of Semiempirical Quantum Mechanics-Based Scoring Function: HSP90 Protein with 4541 Inhibitors and Decoys.

The image shows the ability of SQM-based frame to separate the actives (background: green spheres) from inactives (red spheres) while maintaining a powerful sampling (front: HSP90 crystal complex). Read the full text of the Article at 10.1002/cphc.201900628.

Impressive Enrichment of Semiempirical Quantum Mechanics-Based Scoring Function: HSP90 Protein with 4541 Inhibitors and Decoys.

This paper describes the excellent performance of a newly developed scoring function (SF), based on the semiempirical QM (SQM) PM6-D3H4X method combined with the conductor-like screening implicit solvent model (COSMO). The SQM/COSMO, Amber/GB and nine widely used SFs have been evaluated in terms of ranking power on the HSP90 protein with 72 biologically active compounds and 4469 structurally similar decoys. Among conventional SFs, the highest early and overall enrichment measured by EF1 and AUC% obtained using single-scoring-function ranking has been found for Glide SP and Gold-ASP SFs, respectively (7, 75 % and 3, 76 %). The performance of other standard SFs has not been satisfactory, mostly even decreasing below random values. The SQM/COSMO SF, where P-L structures were optimised at the advanced Amber level, has resulted in a dramatic enrichment increase (47, 98 %), almost reaching the best possible receiver operator characteristic (ROC) curve. The best SQM frame thus inserts about seven times more active compounds into the selected dataset than the best standard SF.

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase†II-Inhibitor Complexes.

Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (Ki ) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R2 of 0.56-0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications.

The role of the σ-holes in stability of non-bonded chalcogenidebenzene interactions: the ground and excited states.

The stability of the T-shaped and stacked complexes of benzene with methanethial (CH2S) and methaneselone (CH2Se) and their difluoro-, dichloro-, dibromo-derivatives is investigated in their ground and first electronic excited states by means of the SCS-ADC2 method. The origin of the stabilization in the ground state is discussed based on the results of calculations performed using the DFT-SAPT method. Calculations show that the stability of the T-shaped conformers increases upon electronic excitation, while it decreases for most of the stacked conformers. Both effects are explained by the changes in the electrostatic potential (ESP) of isolated monomers upon the electronic excitation.

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-[B21H18]- (B21; D3h symmetry) has been synthesized using a simplified strategy compared to that in the literature. While gas-phase complexes of B21 with ß- 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 ß- 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 ß- 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 ß- 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.

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.