Do electrostatic interactions make a difference in physics-based AutoDock4 scoring function?

Physics-based scoring function AutoDock4 is one of the most successfully applied tools in the area of structure-based drug design. However, current scoring functions are still far from being perfect. In a recent work highlighting the strengths and deficiencies of current scoring functions, we discovered that the residual error of ΔGbind predictions made by AutoDock4 is highly correlated to the presence of formally charged fragments in a ligand. In this work, we study how the use of the high-quality atomic charges, applied for contemporary force fields calculation, affects the quality of the experimental ΔGbind prediction by means of AutoDock4. We initially expected that the previously found discrepancy could be attributed to the Gasteiger charges used within AutoDock4. We show that AutoDock4 is, surprisingly, not sensitive to the charges used, and the use of QC-derived atomic charges does not lead to any statistical improvements. We also briefly discuss the role of the explicit empirical hydrogen bond term along with the electrostatic term.

On hidden anisotropy of formally charged fragments.

The proper and precise reproduction of the molecular electrostatic potential (MEP) is crucial to describe correctly electrostatic interactions in molecular modeling. Most of the classical molecular mechanics force fields for biomolecules and drug-like molecules use the atom-centered point charges to describe MEP. However, it has been systematically pointed out in literature that such an approximation is not always enough, and some groups, like amino group or heavy halogens, require the use of anisotropic model for better description of their MEP. At the same time, the formally charged groups have not been as extensively and systematically studied as their neutral counterparts. In this report, we demonstrate that the anisotropic models for formally charged groups do bring improvements in the reference MEP reproduction, that are comparable in magnitude to those for neutral groups.

Assessing How Residual Errors of Scoring Functions Correlate to Ligand Structural Features.

Scoring functions (SFs) are ubiquitous tools for early stage drug discovery. However, their accuracy currently remains quite moderate. Despite a number of successful target-specific SFs appearing recently, up until now, no ideas on how to systematically improve the general scope of SFs have been formulated. In this work, we hypothesized that the specific features of ligands, corresponding to interactions well appreciated by medicinal chemists (e.g., hydrogen bonds, hydrophobic and aromatic interactions), might be responsible, in part, for the remaining SF errors. The latter provides direction to efforts aimed at the rational and systematic improvement of SF accuracy. In this proof-of-concept work, we took a CASF-2016 coreset of 285 ligands as a basis for comparison and calculated the values of scores for a representative panel of SFs (including AutoDock 4.2, AutoDock Vina, X-Score, NNScore2.0, ΔVina RF20, and DSX). The residual error of linear correlation of each SF value, with the experimental values of affinity and activity, was then analyzed in terms of its correlation with the presence of the fragments responsible for certain medicinal chemistry defined interactions. We showed that, despite the fact that SFs generally perform reasonably, there is room for improvement in terms of better parameterization of interactions involving certain fragments in ligands. Thus, this approach opens a potential way for the systematic improvement of SFs without their significant complication. However, the straightforward application of the proposed approach is limited by the scarcity of reliable available data for ligand-receptor complexes, which is a common problem in the field.

Is an Inductive Effect Explicit Account Required for Atomic Charges Aimed at Use within the Force Fields?

Polarization and inductive effects are the concepts that have been widely used in qualitative and even quantitative descriptions of experimentally observed properties in chemistry. The polarization effect has proven to be important in cases of biomolecular modeling though still the vast majority of molecular simulations use the classical non-polarizable force fields. In the last few decades, a lot of effort has been put into promoting the polarization effect and incorporating it into modern force fields and charge calculation methods. In contrast, the inductive effect has not attracted such attention and is effectively absent in both classic and modern force fields. Thus, a question is whether this difference corresponds to the difference in the physical significance of the effects and their explicit account, or is an artifact that should be corrected in the next generation of force fields. The significance of the electronic effects is studied in this paper through the prism of performance of specific models for atomic charge calculation that take into explicit account a nested set of effects: the formal charge, the nearest neighbors, the inductive effect, and finally the model, which takes into account all effects, which are possible to account for using atomic charges. The specific choice for the methods is the following: formal charges, MMFF94 bond charge increments, Dynamic Electronegativity Relaxation (DENR), and RESP. We propose a special scheme for the separate estimation of each particular effect contribution. By pairwise comparing the residual molecular electrostatic potential (MEP) errors of those charge models (aimed at best reproducing the quantum chemical reference MEP), we sequentially revealed how the account of each effect contributes to the better-quality MEP reproduction. The following relative importance of effects was estimated; thus, the natural hierarchy of the effects was established. First, the account of formal charges is of primordial importance. Second, the nearest neighbors account is the next in significance. Third, the explicit account of inductive effect in empirical charge calculation schemes was shown to significantly─both qualitatively and quantitatively─improve the quality of MEP reproduction. Fourth, the contribution of polarization is indirectly assessed. Surprisingly, it is of the order of magnitude of the inductive effect even for the molecular systems, for which it is anticipated to be more significant. Finally, the relative importance of anisotropic effects in neutral molecules was additionally reviewed.

Synthesis of fullerenyl-1,2,3-triazoles by reaction of fullerenyl azide with terminal acetylenes.

Fullerenyltriazoles were synthesized by the interaction of azidofullerene with terminal acetylenes, in which the heterocyclic fragment is directly attached to the fullerene core. The electrochemical studies of the synthesized triazole-containing fullerenes have proved that the potentials of the first reduction peaks are shifted to a less cathodic region compared to unmodified C60. According to theoretical calculations, synthesized fullerene C60 derivatives can be considered as promising acceptor components of organic solar cells.

Assessment of Medication Dosage Adjustment in Hospitalized Patients With Chronic Kidney Disease.

Background Inappropriate medication dosing can cause adverse drug reactions or ineffective therapy due to declined renal function in patients with renal insufficiency. This necessitates proper renal dose adjustment. This study was proposed to evaluate medication dosage adjustment in hospitalized chronic kidney disease (CKD) patients. Methods This study included all CKD patients hospitalized between May 1, 2019, and April 25, 2020, at the Institute of Kidney Disease, Peshawar, Pakistan. The estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease formula, and dose appropriateness was established by evaluating practice with relevant reference books. Results Of the total 1,537 CKD patients, 231 (15.03%) had evidence of dosing error, which was considered for final analysis. Overall, 1,549 drugs were prescribed; 480 (30.99%) drugs required dose adjustment, of which 196 (40.42%) were adjusted properly and the remaining 286 (59.58%) were unadjusted. The most common unadjusted drugs were meropenem, cefepime, ciprofloxacin, and rosuvastatin, whereas captopril, aspirin, bisoprolol, pregabalin, and levofloxacin had the highest percentage of adjusted drugs. On multivariate logistic regression, the number of drugs requiring dosing adjustments and obstructive nephropathy were found to be statistically significant factors that increased the likelihood of the medication dosing errors: a unit increase in the number of drugs requiring dose adjustment increases 5.241 times the likelihood of dosing error. Similarly, the presence of obstructive nephropathy (OR: 0.383; 95% Cl: 0.153-0.960; p = 0.041) was found to be significantly associated with dosing error after adjustment for potential confounding factors. Conclusion The dosing of more than half of the prescribed drugs that required adjustment in CKD patients was not adjusted, which showed that medication dosing errors were high. This highlights the importance of medication prescription according to guidelines in these patients to improve the outcomes of pharmacotherapy.

Synthesis of C60 Fullerene-Quadricyclane Hybrid Compound and Its Preliminary In Vitro Antitumor Activity in Combination with Cisplatin.

This paper describes the authors' preliminary studies directed toward the possibility of the practical implementation of the idea to design efficient antitumor drugs based on hybrid molecules composed of fullerene C60 and quadricyclanes. The essence of the proposed idea is that these hybrid molecules are able to cleave DNA owing to the fullerene moiety they contain and to simultaneously thermally affect tumor cells via cleavage of the carbon-carbon bond in quadricyclanes under the action of Pd and Pt ions. As a result, testing of the cytotoxic activity in vitro for a number of fullerene C60 hybrids with the norbornadiene or quadricyclane moieties against the human T-lymphoblastic leukemia cells (Jurkat cells) in combination of the known cisplatin drug, which was taken as the source of Pt ions, showed a statistically reliable dose-dependent increase in the number of dead cells in each group, which were formed according to the amount of cisplatin added, in comparison with the control, that is, cells treated with cisplatin or quadricyclane fullerene derivatives alone. Indeed, the difference between the percentages of viable cells after treatment with either cisplatin alone or cisplatin in combination with methanofullerene 5 ranged from ∼10% (for Pt (0.015 mkM), 5 (0.015 mkM)) to ∼55% (for Pt (0.03 mkM), 5 (0.045 mkM)).

Iterative Solvers for Empirical Partial Atomic Charges: Breaking the Curse of Cubic Numerical Complexity.

Rational drug design involves a vast amount of computations to get thermodynamically reliable results and often relies on atomic charges as a means to model electrostatic interactions within the system. Computational inefficiency often hampers the development of new and wider dissemination of the known methods; thus, any source to speed up the calculations without a sacrifice in quality is warranted. At the heart of many empirical methods of calculating atomic charges is the solution of a system of linear algebraic equations (SLAE). The classical method of solving SLAE-the Gauss method-has in general case a cubic computational complexity. It is shown that the use of iterative methods for solving SLAE, characteristic to typical empirical atomic charge calculation methods, makes it possible to significantly reduce the amount of calculations and to obtain a computational complexity approaching a quadratic one. Despite the fact that this phenomenon is well-known in numerical methods, iterative solvers surprisingly do not seem to have been systematically applied to calculation of atomic charges via empirical schemes. Another finding is the relative values of the matrix elements, determined by the physical grounds of the interactions within the empirical system, generally lead to SLAE's with well-defined matrices, suited to use with iterative solvers to fasten computation compared to using the noniterative solvers. This finding broadens the applicability range of atomic charges obtained with empirical methods for such cases as, e.g., account of polarizability via "on-the-fly" recalculation of charges in changing surroundings within the force fields in molecular dynamics settings.

Synthesis and Properties of Energy-Rich Methanofullerenes Containing Norbornadiene and Quadricyclane Moieties.

The energy-rich methanofullerenes were synthesized for the first time by the reaction of fullerene C60 with mono- and bisquadricyclane esters of malonic acid. The C-C bond cleavage in the quadricyclane moieties of new hybrid molecules takes place in the presence of catalytic amounts of Cu, Pd, and Pt salts or complexes or SiO2 and is accompanied by heat evolution.

Comparison of conventional cytology and SurePath in split thyroid fine needle aspiration materials.

OBJECTIVE: The aim of the present study was to compare the cytomorphological features and cytopathological diagnoses in thyroid aspiration materials prepared by SurePath® (SP) and conventional cytology (CC). MATERIALS AND METHODS: Fine needle aspiration (FNA) materials from 180 thyroid nodules were divided into two groups to prepare three conventional smears and one SP slide. Twenty-nine cytomorphological features of thyroid lesions were compared in the CC and SP slides. The Kappa coefficiency was determined for each. The cytopathological diagnosis of CC and SP were compared. RESULTS: The feature with the lowest Kappa coefficient was the haemorrhagic background, whereas nuclear molding had the highest Kappa coefficient. The rates of the atypical and suspicious cytopathological diagnostic categories were decreased, whereas the rates of benign and malignant categories were increased in SP. When the cytopathological diagnoses of CC and SP were compared with the histopathological diagnoses of the 31 thyroidectomy materials, the results were similar. CONCLUSION: The common problems seen in CC, such as an excessive number of slides, a haemorrhagic background and air drying artefact in the SP method were not encountered. Through these advantages, the rate of the indeterminate cytopathological diagnosis was low in SP. In addition to those advantages, the increased rates of non-diagnostic cases, the difficulty in evaluating the cytomorphologic features owing to tridimensional structures and the smaller size of the cells and the presence of tridimensional structures uninterpreted microscopically were the disadvantages of SP. The present results showed that SP could be used instead of CC in thyroid cytopathology.

Chitosan gel formulations containing egg yolk oil and epidermal growth factor for dermal burn treatment.

In the present study chitosan based gel formulations containing Egg Yolk Oil (EYO) and Epidermal Growth Factor (EGF) were formulated successfully aiming at enhanced topical treatment of dermal burns the combination of traditional approaches with modern drug delivery systems. Physicochemical properties of the formulations were analyzed and efficacy of the formulations prepared were evaluated versus a commercial product; Silverdin (1% silver sulfadiazine) in vivo on Wistar rats. Burns were generated on the back of the rats and at predetermined time intervals tissue samples were collected and evaluated histologically. The analyses showed that chitosan based gel formulations containing Egg Yolk Oil (E1) and chitosan based gel formulations containing EYO and EGF (M1) formulations seem to be better alternatives for Silverdin with a significant difference (p < 0.05) considering healing ranks of tissue samples.

The effects of timing of aneurysm surgery on vasospasm and mortality in patients with subarachnoid hemorrhage.

OBJECTIVE: The purpose of the present study was to compare the effects of early and late surgery on postoperative vasospasm and mortality in patients with subarachnoid hemorrhage (SAH). METHODS: The data of patients with SAH who underwent aneurysmal clipping at the Kartal Training and Research Hospital between 1999 and 2005 were retrospectively analyzed. The patients who underwent early (0-3 days) and late surgery (> or = 4 days) were evaluated as two groups. Patient outcomes were assessed 1 month after surgery. RESULTS: Of 159 patients (mean age, 49 years; 71 males) with SAHs, 135 (mean age, 51 years; 55 males) underwent early surgery and 24 patients (mean age, 56 years; 16 males) underwent late surgery. The overall postoperative vasospasm rate was 10.7%. The rate of postoperative vasospasm was significantly higher in the late surgery group (41.7%) compared to the early surgery group (5.2%; p < 0.001). There were 15 post-operative deaths (9.4%). The mortality rate in the late surgery group (25.0%) was significantly higher than the early surgery group (6.7%; p = 0.005). CONCLUSIONS: The present study has demonstrated that early surgery is advantageous over late surgery in patients with SAH with lower post-operative vasospasm and mortality rates.

Digital subtraction method for transient evoked otoacoustic emission recording with ipsilateral noise suppression: an application to stimulus artifact reduction.

The suppression of transient evoked otoacoustic emissions (TEOAEs) by continuous ipsilateral noise masking was investigated to explore the feasibility of its use in the elimination of the acoustical stimulus artifact. A reference noise template was obtained by stimulating the ear with identically reproducible digitally synthesized broadband noise. The same noise was used to suppress a TEOAE generated by an ipsilaterally presented click under the same conditions. Digital subtraction of the reference noise from the noise-suppressed TEOAE resulted in obtaining a template of a click artifact for that ear. The results have shown that the digital subtraction method cancels the suppressor noise, enabling the observation of the suppressed TEOAE. The subtraction of the stimulus artifact template from the original TEOAE allowed the recovery of the emission waveform with substantially reduced stimulus artifact, thus enabling the recovery of high-frequency otoacoustic emission components.

Malignant localized fibrous tumor of the pleura occurring in a person environmentally exposed to tremolite asbestos.

A case is presented of a malignant localized pleural fibroma occurring in a 60-year-old Turkish female who was environmentally exposed to tremolite. The tumor was excised but recurred 3 years later when it was again excised. It is possible that more radical surgery at initial presentation with chest wall resection would have been advantageous.