Nejvíce citovaný článek - PubMed ID 26841135
Cuby: An integrative framework for computational chemistry
Single-structure scoring functions have been considered inferior to expensive ensemble free energy methods in predicting protein-ligand affinities. We are revisiting this dogma with the recently developed semiempirical quantum-mechanical (SQM)-based scoring function, SQM2.20, comparing its performance to the standard scoring functions on one hand and state-of-the-art molecular dynamics (MD)-based free-energy methods on the other hand. The comparison is conducted on a well-established Wang data set comprising eight protein targets with 200 ligands. The initial low correlation of SQM2.20 scores with the experimental binding affinities of R2 = 0.21 was improved to R2 = 0.47 by a systematic refinement of the input structures and omission of the ligand deformation energy. Consequently, SQM2.20 representing accurate single-structure scoring functions, exhibited an average performance comparable to that of MD-based methods (R2 = 0.52) and surpassed the performance of standard scoring functions (R2 = 0.26). The per-target analysis highlighted the pivotal role of high-quality input structures on the outcomes of single-structure methods. In the instances where such structures are available, SQM2.20 scoring has been shown to rival or even exceed MD-based methods in predicting protein-ligand binding affinities, while exhibiting significantly reduced computation time.
The quantitative characterization of residue contributions to protein-protein binding across extensive flexible interfaces poses a significant challenge for biophysical computations. It is attributable to the inherent imperfections in the experimental structures themselves, as well as to the lack of reliable computational tools for the evaluation of all types of noncovalent interactions. This study leverages recent advancements in semiempirical quantum-mechanical and implicit solvent approaches embodied in the PM6-D3H4S/COSMO2 method for the development of a hierarchical computational protocols encompassing molecular dynamics, fragmentation, and virtual glycine scan techniques for the investigation of flexible protein-protein interactions. As a model, the binding of insulin to its receptor is selected, a complex and dynamic process that has been extensively studied experimentally. The interaction energies calculated at the PM6-D3H4S/COSMO2 level in ten molecular dynamics snapshots did not correlate with molecular mechanics/generalized Born interaction energies because only the former method is able to describe nonadditive effects. This became evident by the examination of the energetics in small-model dimers featuring all the present types of noncovalent interactions with respect to DFT-D3 calculations. The virtual glycine scan has identified 15 hotspot residues on insulin and 15 on the insulin receptor, and their contributions have been quantified using PM6-D3H4S/COSMO2. The accuracy and credibility of the approach are further supported by the fact that all the insulin hotspots have previously been detected by biochemical and structural methods. The modular nature of the protocol has enabled the formulation of several variants, each tailored to specific accuracy and efficiency requirements. The developed computational strategy is firmly rooted in general biophysical chemistry and is thus offered as a general tool for the quantification of interactions across relevant flexible protein-protein interfaces.
- MeSH
- inzulin metabolismus chemie MeSH
- konformace proteinů MeSH
- lidé MeSH
- receptor inzulinu * chemie metabolismus MeSH
- simulace molekulární dynamiky * MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- inzulin MeSH
- receptor inzulinu * MeSH
A series of 12-phenyl-closo-thiaboranes (12-(4-X-C6H4)-closo-1-SB11H10, where X = OMe (2), X = SMe (3), X = Ph (4), and X = NMe2 (5)) has been prepared. Except for 2, all compounds exhibit a chalcogen bond of thiaborane to the phenyl ring or the neighboring molecule as major supramolecular structural motif. 5, having the strongest (-12.47 kcal/mol) structure-making intermolecular interaction via noncovalent S···π(phenyl) chalcogen bond, was crystallized from different solvents in the form of various solvatopolymorphs. n-Hexane and diethyl ether can be removed from 5 easily upon the formation of a porous material with large cavities (up to 20.5% of the unit cell). This first stable and useful noncovalently bound organic framework material with an ultramicroporous structure exhibits a molecular sieve effect. The selective and repeatable adsorption of CO2 to the material crystallized from n-hexane was explained on the basis of cooperative and consecutive machine-like molecular interactions of quadrupolar CO2 molecule with B-H and amino groups inside rectangular cavities.
- Publikační typ
- časopisecké články MeSH
Machine learning (ML) methods offer a promising route to the construction of universal molecular potentials with high accuracy and low computational cost. It is becoming evident that integrating physical principles into these models, or utilizing them in a Δ-ML scheme, significantly enhances their robustness and transferability. This paper introduces PM6-ML, a Δ-ML method that synergizes the semiempirical quantum-mechanical (SQM) method PM6 with a state-of-the-art ML potential applied as a universal correction. The method demonstrates superior performance over standalone SQM and ML approaches and covers a broader chemical space than its predecessors. It is scalable to systems with thousands of atoms, which makes it applicable to large biomolecular systems. Extensive benchmarking confirms PM6-ML's accuracy and robustness. Its practical application is facilitated by a direct interface to MOPAC. The code and parameters are available at https://github.com/Honza-R/mopac-ml.
- Publikační typ
- časopisecké články MeSH
Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1' and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.
- Klíčová slova
- Schistosoma mansoni, acrylamide inhibitor, cathepsin B, cysteine protease, drug target, parasite,
- MeSH
- kathepsin B * antagonisté a inhibitory metabolismus MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- Schistosoma mansoni * enzymologie účinky léků MeSH
- schistosomicidy farmakologie chemie MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kathepsin B * MeSH
- schistosomicidy MeSH
Accurate estimation of protein-ligand binding affinity is the cornerstone of computer-aided drug design. We present a universal physics-based scoring function, named SQM2.20, addressing key terms of binding free energy using semiempirical quantum-mechanical computational methods. SQM2.20 incorporates the latest methodological advances while remaining computationally efficient even for systems with thousands of atoms. To validate it rigorously, we have compiled and made available the PL-REX benchmark dataset consisting of high-resolution crystal structures and reliable experimental affinities for ten diverse protein targets. Comparative assessments demonstrate that SQM2.20 outperforms other scoring methods and reaches a level of accuracy similar to much more expensive DFT calculations. In the PL-REX dataset, it achieves excellent correlation with experimental data (average R2 = 0.69) and exhibits consistent performance across all targets. In contrast to DFT, SQM2.20 provides affinity predictions in minutes, making it suitable for practical applications in hit identification or lead optimization.
- MeSH
- ligandy MeSH
- proteiny * metabolismus MeSH
- racionální návrh léčiv * MeSH
- termodynamika MeSH
- vazba proteinů MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ligandy MeSH
- proteiny * MeSH
In this theoretical study, we set out to demonstrate the substitution effect of PEDOT analogues on planarity as an intrinsic indicator for electronic performance. We perform a quantum mechanical (DFT) study of PEDOT and analogous model systems and demonstrate the usefulness of the ωB97X-V functional to simulate chalcogen bonds and other noncovalent interactions. We confirm that the chalcogen bond stabilizes the planar conformation and further visualize its presence via the electrostatic potential surface. In comparison to the prevalent B3LYP, we gain 4-fold savings in computational time and simulate model systems of up to a dodecamer. Implications for design of conductive polymers can be drawn from the results, and an example for self-doped polymers is presented where modulation of the strength of the chalcogen bond plays a significant role.
- Publikační typ
- časopisecké články MeSH
Spectroscopic characteristics of Me3Si-H···Y complexes (Y = ICF3, BrCN, and HCN) containing a hydridic hydrogen were determined experimentally by low-temperature IR experiments based on the direct spectral measurement of supersonically expanded intermediates on a cold substrate or by the technique of argon-matrix isolation as well as computationally at harmonic and one-dimensional anharmonic levels. The computations were based on DFT-D, MP2, MP2-F12, and CCSD(T)-F12 levels using various extended AO basis sets. The formation of all complexes related to the redshift of the Si-H stretching frequency upon complex formation was accompanied by an increase in its intensity. Similar results were obtained for another 10 electron acceptors of different types, positive σ-, π-, and p-holes and cations. The formation of HBe-H···Y complexes, studied only computationally and again containing a hydridic hydrogen, was characterized by the blueshift of the Be-H stretching frequency upon complexation accompanied by an increase in its intensity. The spectral shifts and stabilization energies obtained for all presently studied hydridic H-bonded complexes were comparable to those in protonic H-bonded complexes, which has prompted us to propose a modification of the existing IUPAC definition of H-bonding that covers, besides the classical protonic form, the non-classical hydridic and dihydrogen forms.
- Publikační typ
- časopisecké články MeSH
Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.
- Klíčová slova
- Cathepsin K, azadipeptide nitrile, cyanohydrazide warhead, protease inhibitor, structure,
- MeSH
- hydraziny chemie farmakologie MeSH
- inhibitory proteas chemie farmakologie MeSH
- kathepsin K antagonisté a inhibitory metabolismus MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- nádorové buňky kultivované MeSH
- nitrily chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CTSK protein, human MeSH Prohlížeč
- hydraziny MeSH
- inhibitory proteas MeSH
- kathepsin K MeSH
- nitrily MeSH
Community efforts in the computational molecular sciences (CMS) are evolving toward modular, open, and interoperable interfaces that work with existing community codes to provide more functionality and composability than could be achieved with a single program. The Quantum Chemistry Common Driver and Databases (QCDB) project provides such capability through an application programming interface (API) that facilitates interoperability across multiple quantum chemistry software packages. In tandem with the Molecular Sciences Software Institute and their Quantum Chemistry Archive ecosystem, the unique functionalities of several CMS programs are integrated, including CFOUR, GAMESS, NWChem, OpenMM, Psi4, Qcore, TeraChem, and Turbomole, to provide common computational functions, i.e., energy, gradient, and Hessian computations as well as molecular properties such as atomic charges and vibrational frequency analysis. Both standard users and power users benefit from adopting these APIs as they lower the language barrier of input styles and enable a standard layout of variables and data. These designs allow end-to-end interoperable programming of complex computations and provide best practices options by default.
- Publikační typ
- časopisecké články MeSH
