To facilitate the identification of novel MAO-B inhibitors, we elaborated a consolidated computational approach, including a pharmacophoric atom-based 3D quantitative structure-activity relationship ...(QSAR) model, activity cliffs, fingerprint, and molecular docking analysis on a dataset of 126 molecules. An AAHR.2 hypothesis with two hydrogen bond acceptors (A), one hydrophobic (H), and one aromatic ring (R) supplied a statistically significant 3D QSAR model reflected by the parameters: R
= 0.900 (training set); Q
= 0.774 and Pearson's R = 0.884 (test set), stability s = 0.736. Hydrophobic and electron-withdrawing fields portrayed the relationships between structural characteristics and inhibitory activity. The quinolin-2-one scaffold has a key role in selectivity towards MAO-B with an AUC of 0.962, as retrieved by ECFP4 analysis. Two activity cliffs showing meaningful potency variation in the MAO-B chemical space were observed. The docking study revealed interactions with crucial residues TYR:435, TYR:326, CYS:172, and GLN:206 responsible for MAO-B activity. Molecular docking is in consensus with and complementary to pharmacophoric 3D QSAR, ECFP4, and MM-GBSA analysis. The computational scenario provided here will assist chemists in quickly designing and predicting new potent and selective candidates as MAO-B inhibitors for MAO-B-driven diseases. This approach can also be used to identify MAO-B inhibitors from other libraries or screen top molecules for other targets involved in suitable diseases.
The human immunodeficiency virus type 1 (HIV-1), one of the leading causes of infectious death globally, generates severe damages to people's immune systems and makes them susceptible to serious ...diseases. To date, there are no drugs that completely remove HIV from the body. This paper focuses on screening 224,205 natural compounds of ZINC15 NPs subset to identify those with bioactivity similar to non-nucleoside reverse transcriptase inhibitors (NNRTIs) as promising candidates to treat HIV-1. To reach the goal, an in silico approach involving 3D-similarity search, ADMETox, HIV protein-inhibitor prediction, docking, and MM-GBSA free-binding energies was trained. The FDA-approved HIV drugs, efavirenz, etravirine, rilpivirine, and doravirine, were used as queries. The prioritized compounds were subjected to ADMETox, docking, and MM-GBSA studies against HIV-1 reverse transcriptase (RT). Lys101, Tyr181, Tyr188, Trp229, and Tyr318 residues and free-binding energies have proved that ligands can stably bind to HIV-1 RT. Three natural products (ZINC37538901, ZINC38321654, and ZINC67912677) containing oxan and oxolan rings with hydroxyl substituents and one (ZINC2103242) having 3,6,7,8-tetrahydro-2H-pyrido1,2-apyrazine-1,4-dione core exhibited comparable profiles to etravirine and doravirine, with ZINC2103242 being the most promising anti-HIV candidate in terms of drug metabolism and safety profile. These findings may open new avenues to guide the rational design of novel HIV-1 NNRTIs.
The main study’s purpose is to detect novel natural products (NPs) that are potentially selective MAO-B inhibitors and, additionally, to computationally reposition the marketed drugs with a new ...therapeutic role for Parkinson’s disease. To reach the goals, 3D similarity search, docking, ADMETox, and drug repurposing approaches were employed. Thus, an unbiased benchmarking dataset was built including selective and nonselective inhibitors for MAO-B compliant with both ligand- and structure-based virtual screening approaches. A retrospective and prospective mining scenario was applied to SPECS NP and DrugBank databases to detect novel scaffolds with potential benefits for Parkinson’s disease patients. Out of the three best selected natural products, cardamomin showed excellently predicted drug-like properties, superior pharmacological profile, and specific interactions with MAO-B active site, indicating a potential selectivity over MAO-B. Two marketed drugs, fenamisal and monobenzone, were proposed as promising candidates repurposed for Parkinson’s disease. The application of shape, physicochemical, and electrostatic similarity searches protocol emerged as a plausible solution to explore MAO-B inhibitors selectivity. This protocol might serve as a rewarding tool in early drug discovery and can be extended to other protein targets.
Graphic abstract
In the context of unknowing the experimental structure for histamine H
3
receptor, which is a potential therapeutical target for numerous disorders and diseases, the theoretical methods can bring ...light and necessary information for a better understanding of the pharmacological implications of the aforementioned receptor. Thus, a homology model of human histamine H
3
receptor was built, and SiteMap was used for the identification of potential binding sites. The top-ranked site (the putative binding site) is found in a niche surrounded by TM3, TM5, TM6, and TM7 transmembranes, and it contains the following important amino acids, Asp114 (3.32) and Trp371 (6.48), which are believed to be the key residues, responsible for ligands binding and receptor activation. The docking programs (Glide and Induced Fit) were involved and by the superposition of the best poses obtained, a structure-based protein-ligand pharmacophore model with one hydrogen bond donor, one hydrogen bond acceptor, and one positive ionic feature was developed. The PHASE software, a ligand-based method, was useful in order to validate the 3D pharmacophore hypothesis, by getting a significant Quantitative Structure Activity Relationship (QSAR) model (with
R
2
= 0.918 for training set and
Q
2
= 0.828 for test set) for the compounds taken in the study. Further, the pharmacophore model can be used in virtual screening experiments to identify new potent ligands for histamine H
3
receptor.
Lately, the cancers related with abnormal hedgehog (Hh) signalling pathway are targeted by smoothened (SMO) receptor inhibitors that are rapidly developing. Still, the problems of known inhibitors ...such as severe side effects, weak potency against solid tumors or even the acquired resistance need to be overcome by developing new suitable inhibitors. To explore the structural requirements of antagonists needed for SMO receptor inhibition, pharmacophore mapping, 3D-QSAR models, database screening and docking studies were performed. The best selected pharmacophore hypothesis based on which statistically significant atom-based 3D-QSAR model was developed (R2 = = 0.856, Q2 = 0.611 and Pearson-R = 0.817), was further subjected to dataset screening in order to evaluate its ability to prioritize active compounds over decoys. The efficiency of one four-points pharmacophore hypothesis (AAHR.524) was observed based on good evaluation metrics such as the area under the curve (0.795), and weighted average precision (0.835), suggesting that the model is trustworthy in predicting novel inhibitors against SMO receptor.
nema
Abstract
Context: Glycogen synthase kinase-3 (GSK-3) overactivity was correlated with several pathologies including type 2 diabetes mellitus, Alzheimer's disease, cancer, inflammation, obesity, etc.
...Objective: The aim of the current investigation was to model the inhibitory activity of maleimide derivatives - inhibitors of GSK-3, to evaluate the impact of alignment on statistical performances of the Quantitative Structure--Activity Relationship (QSAR) and the effect of the template on shape-similarity - binding affinity relationship.
Materials and methods: Dragon descriptors were used to generate Projection to Latent Structures (PLS) models in order to identify the structural prerequisites of maleimides to inhibit GSK-3. Additionally, shape/volume structural analysis of binding site interactions was evaluated.
Results: Reliable statistics \def\newpage{\vfill \break }
\nopagenumbers
$ {\rm R}_{{\rm Y(CUM)}}^2 $
\newpage \end = 0.938/0.920, \def\newpage{\vfill \break }
\nopagenumbers
$ {\rm Q}_{{\rm Y(CUM)}}^2 $
\newpage \end = 0.866/0.838 for aligned and alignment free QSAR models and significant (Pearson, Kendall and Spearman) correlations between shape/volume similarity and affinities were obtained.
Discussion and conclusions: The crucial structural features modulating the activity of maleimides include topology, charge, geometry, 2D autocorrelations, 3D-MoRSE as well as shape/volume and molecular flexibility.
In this research we conducted a systematic review of the characteristics of social-emotional development in adolescents and the extent to which they are influenced or correlated by the concept of ...friendship. We also investigated the influence of socio-emotional traits on the quality of friendship in adolescence. To achieve this, we searched for published scientific studies from several major databases. . The main keywords used for this study were "Adolescence", "Friendship", "Social-emotional development", "Social development", "Emotions". We initially identified 123 studies with the mentioned keywords and we decided that 73 studies are eligible for the purpose of this research. Those were read and analyzed in full-text format. Following this stage, we decided to include 29 studies in the review. We identified a large diversity in the sample of participants presented in the study, with a total of 11,684 participants; from the total of eligible studies, three are systematic reviews that have explored our key concepts (friendship and concepts related to social-emotional development). Through this systematic review, we were able to summarize the current data and knowledge about friendship, social-emotional development and relationships between the two, during adolescence.
Neutrophil elastase, a serine proteinase from the chymotrypsin family, has been the object of comprehensive experimental and theoretical studies to develop efficient human neutrophil elastase ...inhibitors. The serine protease has been linked to the pathology of a variety of inflammatory diseases, making it an attractive target for the development of anti-inflammatory compounds. In this work, we have built a common binding model of the 2-pyridin-3-yl-benzod1,3oxazin-4-one derivatives into the human neutrophil elastase binding site. This was accomplished through a comparative conformational analysis (using OMEGA, HYPERCHEM, and MOPAC software) of 2-pyridin-3-yl-benzod1,3oxazin-4-one inhibitors followed by rigid and flexible molecular docking (by the FRED and GLIDE programs) into the target protein. We conclude that OMEGA software generates the most representative conformers to model the protein-ligand interactions.
Neonicotinoids are the fastest-growing class of insecticides successfully applied in plant protection, human and animal health care. The significant resistance increases led to the urgent need for ...alternative new neonicotinoids, with improved insecticidal activity. We performed molecular docking to describe a common binding mode of neonicotinoids into the nicotinic acetylcholine receptor, and to select the appropriate conformations to derive models. These were further used in a QSAR study employing both linear and nonlinear approaches to model the inhibitory activity against the
Cowpea aphids
. Linear modeling was performed by multiple linear regression and partial least squares and nonlinear modeling by artificial neural networks and support vector machine methods. The OECD principles were considered for QSAR models validation. Robust models with predictive power were found for neonicotinoid diverse structures. Based on our QSAR and docking outcomes, five new insecticides were predicted, according to the model applicability domain, the ligand efficiencies, and the binding mode. Therefore, the developed models can be confidently used for the prediction of the insecticidal activity of new chemicals, saving a substantial amount of time and money and, also, contributing to the chemical risk assessment.
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