scholarly journals How can SHAP values help to shape metabolic stability of chemical compounds?

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Agnieszka Wojtuch ◽  
Rafał Jankowski ◽  
Sabina Podlewska
Keyword(s):  
Web Service ◽  
Chemical Compounds ◽  
Structural Features ◽  
Metabolic Stability ◽  
Structural Modifications ◽  
Pharmacokinetic Properties ◽  
Biological Target ◽  
Future Drug ◽  
Living Organisms ◽  
Great Complexity

Abstract Background Computational methods support nowadays each stage of drug design campaigns. They assist not only in the process of identification of new active compounds towards particular biological target, but also help in the evaluation and optimization of their physicochemical and pharmacokinetic properties. Such features are not less important in terms of the possible turn of a compound into a future drug than its desired affinity profile towards considered proteins. In the study, we focus on metabolic stability, which determines the time that the compound can act in the organism and play its role as a drug. Due to great complexity of xenobiotic transformation pathways in the living organisms, evaluation and optimization of metabolic stability remains a big challenge. Results Here, we present a novel methodology for the evaluation and analysis of structural features influencing metabolic stability. To this end, we use a well-established explainability method called SHAP. We built several predictive models and analyse their predictions with the SHAP values to reveal how particular compound substructures influence the model’s prediction. The method can be widely applied by users thanks to the web service, which accompanies the article. It allows a detailed analysis of SHAP values obtained for compounds from the ChEMBL database, as well as their determination and analysis for any compound submitted by a user. Moreover, the service enables manual analysis of the possible structural modifications via the provision of analogous analysis for the most similar compound from the ChEMBL dataset. Conclusions To our knowledge, this is the first attempt to employ SHAP to reveal which substructural features are utilized by machine learning models when evaluating compound metabolic stability. The accompanying web service for metabolic stability evaluation can be of great help for medicinal chemists. Its significant usefulness is related not only to the possibility of assessing compound stability, but also to the provision of information about substructures influencing this parameter. It can assist in the design of new ligands with improved metabolic stability, helping in the detection of privileged and unfavourable chemical moieties during stability optimization. The tool is available at https://metstab-shap.matinf.uj.edu.pl/.

Designed Synthesis of Diversely Substituted Hydantoins and Hydantoin-Based Hybrid Molecules: A Personal Account

Synlett ◽  
2021 ◽  
Author(s):  
Vinod Kumar
Keyword(s):  
Clinical Applications ◽  
Point Of View ◽  
Biological Functions ◽  
Personal Account ◽  
Pharmacological Activities ◽  
Structural Modifications ◽  
Hybrid Molecules ◽  
Biological Target ◽  
Designed Synthesis ◽  
Mixed Mechanism

Hydantoin and its analogs such as thiohydantoin and iminohydantoin have received substantial attention both from a chemical and biological point of view. Several compounds of this class have shown useful pharmacological activities such as anticonvulsant, antitumor, antiarrhythmic, herbicidal, and others that lead in some cases to clinical applications. Because of broad-spectrum activities, intensive research efforts have been dedicated in industry and academia to the synthesis and structural modifications of hydantoin and its derivatives. Realizing the importance of hydantoin in organic and medicinal chemistry, we also initiated a research program to successfully design and develop the new routes/methods resulting in the formation of hydantoin, thiohydantoin, and iminohydantoin substituted at different positions particularly at the N-1 position without following protection-deprotection strategy. Given the fact that the combination of two or more pharmacophoric groups may lead to hybrid molecules which result in a mixed mechanism of action on the biological target. We, therefore, further extended the developed strategy for the synthesis of new types of hydantoin-based hybrid molecules by combining hydantoin with a triazole, isoxazoline, and phosphate scaffolds as another pharmacophoric group to exploit diverse biological functions.

Tanshinone IIA: Pharmacology, total synthesis, and progress in structure-modifications

2021 ◽  
Vol 28 ◽  
Author(s):  
Xing Huang ◽  
Hao Deng ◽  
Qing-kun Shen ◽  
Zhe-Shan Quan
Keyword(s):  
Herbal Medicine ◽  
Total Synthesis ◽  
Chinese Herbal Medicine ◽  
Biological Activities ◽  
Structural Features ◽  
Tanshinone Iia ◽  
Structural Modifications ◽  
Chinese Herbal ◽  
Bioactive Constituent

: Tanshinone IIA, a major bioactive constituent of Danshen, a Chinese herbal medicine, has gained extensive exploration owing to its unique structural features and multiple promising biological activities. This review focuses on the pharmacology, total synthesis, and structural modifications of tanshinone IIA. We hope this review will contribute to a better understanding of the progress in the field and provide constructive suggestions for further study of tanshinone IIA.

scholarly journals Recognition of Pharmacological Bi-Heterocyclic Compounds by Using Terahertz Time Domain Spectroscopy and Chemometrics

Sensors ◽  
2019 ◽  
Vol 19 (15) ◽  
pp. 3349 ◽  
Author(s):  
Maciej Roman Nowak ◽  
Rafał Zdunek ◽  
Edward Pliński ◽  
Piotr Świątek ◽  
Małgorzata Strzelecka ◽  
...  
Keyword(s):  
Heterocyclic Compounds ◽  
Chemical Compounds ◽  
Functional System ◽  
Support Vector ◽  
Optimal Parameters ◽  
Terahertz Time Domain Spectroscopy ◽  
Kernel Support Vector Machine ◽  
Inflammatory Drugs ◽  
Living Organisms

In this study, we presented the concept and implementation of a fully functional system for the recognition of bi-heterocyclic compounds. We have conducted research into the application of machine learning methods to correctly recognize compounds based on THz spectra, and we have described the process of selecting optimal parameters for the kernel support vector machine (KSVM) with an additional `unknown’ class. The chemical compounds used in the study contain a target molecule, used in pharmacy to combat inflammatory states formed in living organisms. Ready-made medical products with similar properties are commonly referred to as non-steroidal anti-inflammatory drugs (NSAIDs) once authorised on the pharmaceutical market. It was crucial to clearly determine whether the tested sample is a chemical compound known to researchers or is a completely new structure which should be additionally tested using other spectrometric methods. Our approach allows us to achieve 100% accuracy of the classification of the tested chemical compounds in the time of several milliseconds counted for 30 samples of the test set. It fits perfectly into the concept of rapid recognition of bi-heterocyclic compounds without the need to analyse the percentage composition of compound components, assuming that the sample is classified in a known group. The method allows us to minimize testing costs and significant reduction of the time of analysis.

scholarly journals The Radioprotective Effect of Procaine and Procaine-Derived Product Gerovital H3 in Lymphocytes from Young and Aged Individuals

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Anca Ungurianu ◽  
Denisa Margina ◽  
Claudia Borsa ◽  
Cristina Ionescu ◽  
Gudrun von Scheven ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Chemical Compounds ◽  
Dna Strand Breaks ◽  
Peripheral Blood Mononuclear ◽  
Strand Breaks ◽  
Young Subjects ◽  
Living Organisms ◽  
Dna Strand

Ionizing radiation induces genomic instability in living organisms, and several studies reported an ageing-dependent radiosensitivity. Chemical compounds, such as scavengers, radioprotectors, and modifiers, contribute to reducing the radiation-associated toxicity. These compounds are often antioxidants, and therefore, in order to be effective, they must be present before or during exposure to radiation. However, not all antioxidants provide radioprotection. In this study, we investigated the effects of procaine and of a procaine-based product Gerovital H3 (GH3) on the formation of endogenous and X-ray-induced DNA strand breaks in peripheral blood mononuclear cells (PBMCs) isolated from young and elderly individuals. Interestingly, GH3 showed the strongest radioprotective effects in PBMCs from young subjects, while procaine reduced the endogenous amount of DNA strand breaks more pronounced in aged individuals. Both procaine and GH3 inhibited lipid peroxidation, but procaine was more effective in inhibiting mitochondria free radicals’ generation, while GH3 showed a higher antioxidant action on macrophage-induced low-density lipoprotein oxidation. Our findings provide new insights into the mechanisms underlying the distinct effects of procaine and GH3 on DNA damage.

scholarly journals In SilicoScreening of the Library of Pyrimidine Derivatives as Thymidylate Synthase Inhibitors for Anticancer Activity

2009 ◽  
Vol 6 (3) ◽  
pp. 665-672 ◽  
Author(s):  
A. G. Nerkar ◽  
S. A. Ghone ◽  
A. K. Thaker
Keyword(s):  
Thymidylate Synthase ◽  
In Silico ◽  
Active Metabolite ◽  
Heterocyclic Ring ◽  
Pyrimidine Derivatives ◽  
Structural Modifications ◽  
Pharmacokinetic Properties ◽  
Adme Properties ◽  
Thymidylate Synthase Inhibitors ◽  
Potential Inhibitors

We here report the virtual screening of several series of pyrimidine derivatives forin silicoThymidylate Synthase (TS) inhibition to arrive at possible potential inhibitors of TS with acceptable pharmacokinetic or ADME (Absorption, Distribution, Metabolism and Excretion) properties. Library of the molecules was constructed based upon structural modifications of pyrimidines nucleus. Structural modifications in descending order were performed for the series of pyrimidines,vizfrom pyrimidines with five membered heterocyclic ring to pyrimidines with four membered heterocyclic ring to simple pyrimindine carboxylates in an order to arrive at pyrimidines with better inhibition scores (G-Scores) as compared with Raltitrexed (RTX) and active metabolite of 5-Fluorouracil (5-FUMP). The molecules with betterG-Scores were subjected to predict pharmacokinetic or ADME properties. The molecules with acceptable ADME properties and betterG-Scores were prioritized for synthesis and anticancer evaluation. Three molecules from pyrimidine carboxylate series PIC1-31were found acceptable withG-Scores and pharmacokinetic properties. Thus a library of pyrimidine derivatives was constructed based upon the feasibility of synthesis and in silico screened to prioritize the molecules and to obtain potential lead molecules as TS inhibitors.

Assessing the Prediction Quality of the Anti-SARS-CoV-2 Activity Using the D3Targets-2019-nCoV Web Service

2020 ◽  
Vol 3 (4) ◽  
pp. e00140
Author(s):  
N.S. Ionov ◽  
P.V. Pogodin ◽  
V.V. Poroikov
Keyword(s):  
Molecular Docking ◽  
Web Service ◽  
Scoring Function ◽  
Chemical Compounds ◽  
Structural Similarity ◽  
Similarity Score ◽  
Test Set ◽  
Target Proteins ◽  
Similarity Assessment

The D3Targets-2019-nCoV web service predicting the interaction of chemical compounds with SARS-CoV-2 virus proteins and human proteins involved in the pathogenesis of COVID-19 by structural similarity and molecular docking was evaluated. The quality of the prediction was assessed as a balanced accuracy, which was calculated based on the results of the prediction for the structures of chemical compounds from the test set we compiled. The test set consisted of 35 active and 59 inactive molecules, including compounds with the experimetnaly confirmed absence of activity against the selected targets and compounds active against SARS-CoV-2 targets, not presented in the CoViLigands database. The authors of the analyzed web service did not indicate the thresholds for the values of the similarity score and the docking scoring function, using which it would be possible to reliably divide the compounds into active and inactive with respect to target proteins. Therefore, we assessed the balanced accuracy of the predictive methods D3Targets-2019-nCoV at various thresholds for cutting off active substances from inactive ones. Using our test set it was found that the highest value of balanced accuracy (0.59) was achieved when choosing active molecules based on the results of 2D similarity assessment (cutoff threshold was 46%). Assessment of 3D similarity did not allow achieving balanced accuracy values exceeding 0.5. It is shown that using the 2Dх3D integral similarity assessment recommended by the authors, the maximum value of the balanced accuracy 0.57 was achieved at a threshold of 31%. The calculated balanced accuracy for molecular docking results does not exceed 0.51. On the case study for the tideglusib, it was shown that the values of the scoring function for two target proteins, the activity against which was confirmed in the experiment (3CLpro and GSK3B), do not differ significantly from the values of the scoring function for the remaining 44 targets were not confirmed.

scholarly journals Experimental diagenesis: insights into aragonite to calcite transformation of <i>Arctica islandica</i> shells by hydrothermal treatment

2017 ◽  
Vol 14 (6) ◽  
pp. 1461-1492 ◽  
Author(s):  
Laura A. Casella ◽  
Erika Griesshaber ◽  
Xiaofei Yin ◽  
Andreas Ziegler ◽  
Vasileios Mavromatis ◽  
...  
Keyword(s):  
Hydrothermal Alteration ◽  
Fossil Record ◽  
Marine Invertebrates ◽  
Structural Features ◽  
Geochemical Data ◽  
Replacement Reaction ◽  
Bulk Analysis ◽  
Arctica Islandica ◽  
Experimental Conditions ◽  
Living Organisms

Abstract. Biomineralised hard parts form the most important physical fossil record of past environmental conditions. However, living organisms are not in thermodynamic equilibrium with their environment and create local chemical compartments within their bodies where physiologic processes such as biomineralisation take place. In generating their mineralised hard parts, most marine invertebrates produce metastable aragonite rather than the stable polymorph of CaCO3, calcite. After death of the organism the physiological conditions, which were present during biomineralisation, are not sustained any further and the system moves toward inorganic equilibrium with the surrounding inorganic geological system. Thus, during diagenesis the original biogenic structure of aragonitic tissue disappears and is replaced by inorganic structural features. In order to understand the diagenetic replacement of biogenic aragonite to non-biogenic calcite, we subjected Arctica islandica mollusc shells to hydrothermal alteration experiments. Experimental conditions were between 100 and 175 °C, with the main focus on 100 and 175 °C, reaction durations between 1 and 84 days, and alteration fluids simulating meteoric and burial waters, respectively. Detailed microstructural and geochemical data were collected for samples altered at 100 °C (and at 0.1 MPa pressure) for 28 days and for samples altered at 175 °C (and at 0.9 MPa pressure) for 7 and 84 days. During hydrothermal alteration at 100 °C for 28 days most but not the entire biopolymer matrix was destroyed, while shell aragonite and its characteristic microstructure was largely preserved. In all experiments up to 174 °C, there are no signs of a replacement reaction of shell aragonite to calcite in X-ray diffraction bulk analysis. At 175 °C the replacement reaction started after a dormant time of 4 days, and the original shell microstructure was almost completely overprinted by the aragonite to calcite replacement reaction after 10 days. Newly formed calcite nucleated at locations which were in contact with the fluid, at the shell surface, in the open pore system, and along growth lines. In the experiments with fluids simulating meteoric water, calcite crystals reached sizes up to 200 µm, while in the experiments with Mg-containing fluids the calcite crystals reached sizes up to 1 mm after 7 days of alteration. Aragonite is metastable at all applied conditions. Only a small bulk thermodynamic driving force exists for the transition to calcite. We attribute the sluggish replacement reaction to the inhibition of calcite nucleation in the temperature window from ca. 50 to ca. 170 °C or, additionally, to the presence of magnesium. Correspondingly, in Mg2+-bearing solutions the newly formed calcite crystals are larger than in Mg2+-free solutions. Overall, the aragonite–calcite transition occurs via an interface-coupled dissolution–reprecipitation mechanism, which preserves morphologies down to the sub-micrometre scale and induces porosity in the newly formed phase. The absence of aragonite replacement by calcite at temperatures lower than 175 °C contributes to explaining why aragonitic or bimineralic shells and skeletons have a good potential of preservation and a complete fossil record.

scholarly journals Screening for a Potential Therapeutic Agent from the Herbal Formula in the 4th Edition of the Chinese National Guidelines for the Initial-Stage Management of COVID-19 via Molecular Docking

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Yue Sun ◽  
Angela Wei Hong Yang ◽  
Andrew Hung ◽  
George Binh Lenon
Keyword(s):  
Molecular Docking ◽  
Therapeutic Agent ◽  
Chemical Compounds ◽  
Pharmacokinetic Property ◽  
Herbal Formula ◽  
Stage Management ◽  
National Guidelines ◽  
Initial Stage ◽  
Pharmacokinetic Properties ◽  
Atractylenolide Iii

Background. COVID-19 caused by SARS-CoV-2 infection has been spreading through many countries since the end of 2019. The 4th edition of the national guidelines for the management of COVID-19 provides an herbal formula with 9 herbs for its management. Aim of Study. We aimed to predict the mechanism of binding of SARS-CoV-2 and SARS-CoV spike glycoproteins with angiotensin-converting enzyme 2 (ACE2) to provide a molecular-level explanation of the higher pathogenicity of SARS-CoV-2 and to identify protein sites which may be targeted by therapeutic agents to disrupt virus-host interactions. Subsequently, we aimed to investigate the formula for the initial-stage management to identify a therapeutic agent with the most likely potential to become pharmaceutical candidate for the management of this disease. Materials and Methods. GenBank and SWISS-MODEL were applied for model creation. ClusPro was used for protein-protein docking. PDBePISA was applied for identification of possible binding sites. TCMSP was employed for identification of the chemical compounds. AutoDock Vina together with PyRx was used for the prediction and evaluation of binding pose and affinity to ACE2. SwissADME and PreADME were applied to screening and prediction of the pharmacokinetic properties of the identified chemical compounds. PyMOL was used to visualise the structural models of SARS-CoV-2 and SARS-CoV spike glycoproteins complexed to ACE2 and to examine their interactions. Results. SARS-CoV-2 had two chains (labelled chains B and C) which were predicted to bind with ACE2. In comparison, the SARS-CoV had only one chain (labelled chain C) predicted to bind with ACE2. The spike glycoproteins of both viruses were predicted to bind with ACE2 via position 487. Molecular docking screening and pharmacokinetic property prediction of the herbal compounds indicated that atractylenolide III (−9.1 kcal/mol) from Atractylodes lancea (Thunb.) Dc. (Cangzhu) may be a candidate therapeutic agent for initial-stage management. Conclusions. Atractylenolide III is predicted to have a strong binding affinity with ACE2 and eligible pharmacokinetic properties, anti-inflammatory effects and antiviral effects in in vitro study, and high distribution on the lungs in in vivo study.

Triazolopyrimidine Nuclei: Privileged Scaffolds for Developing Antiviral Agents with a Proper Pharmacokinetic Profile

2021 ◽  
Vol 28 ◽  
Author(s):  
Tommaso Felicetti ◽  
Maria Chiara Pismataro ◽  
Violetta Cecchetti ◽  
Oriana Tabarrini ◽  
Serena Massari
Keyword(s):  
Viral Infections ◽  
Biological Activities ◽  
Antiviral Agents ◽  
Pharmacokinetic Profile ◽  
Binding Mode ◽  
Biologically Active ◽  
Dna Viruses ◽  
Pharmacokinetic Properties ◽  
Biological Target ◽  
Synthetic Methodologies

Viruses are a continuing threat to global health. The lack or limited therapeutic armamentarium against some viral infections and increasing drug resistance issues make the search for new antiviral agents urgent. In recent years, a growing literature highlighted the use of triazolopyrimidine (TZP) heterocycles in the development of antiviral agents, with numerous compounds that showed potent antiviral activities against different RNA and DNA viruses. TZP core represents a privileged scaffold for achieving biologically active molecules, thanks to: i) the synthetic feasibility that allows to variously functionalize TZPs in the different positions of the nucleus, ii) the ability of TZP core to establish multiple interactions with the molecular target, and iii) its favorable pharmacokinetic properties. In the present review, after mentioning selected examples of TZP-based compounds with varied biological activities, we will focus on those antivirals that appeared in the literature in the last 10 years. Approaches used for their identification, the hit-to-lead studies, and the emerged structure-activity relationship will be described. A mention of the synthetic methodologies to prepare TZP nuclei will also be given. In addition, their mechanism of action, the binding mode within the biological target, and pharmacokinetic properties will be analyzed, highlighting the strengths and weaknesses of compounds based on the TZP scaffold, which is increasingly used in medicinal chemistry.

Dimension of Molecules of Compounds of Biogenic Elements

2019 ◽  
pp. 127-153
Keyword(s):  
Chemical Bond ◽  
Chemical Elements ◽  
Chemical Compounds ◽  
Building Blocks ◽  
Chemical Activity ◽  
Biogenic Elements ◽  
Higher Dimension ◽  
Complex Molecules ◽  
P Elements ◽  
Living Organisms

Chemical compounds of biogenic elements are considered (i.e., chemical elements present in living organisms and ensuring the successful functioning of their various organs and systems). Biogenic elements are divided into s-, p-, and d-elements, in which respectively are completed with s-, p-, and d-electronic orbitals. In each of these groups, the structure of compounds of biogenic elements is investigated, and the dimension of the corresponding molecules is determined. It is proved that s- and d-biogenic elements exhibit increased chemical activity (higher than the standard valence) due to participation in the formation of a chemical bond of electrons of the preceding level. This leads to the creation of complex molecules of higher dimension. The chemical compounds of biogenic p-elements, which are the building blocks for the formation of biomolecules (elements of life), will be specifically investigated in subsequent chapters.

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