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Journal of Computer-aided Molecular Design

Yvonne Connolly Martin
Although log P is now recognized to be a key factor that determines the bioactivity of a molecule, the focus of medicinal chemists on hydrophobicity and log P started with the quantitative structure-activity relationships (QSAR) publications of Hansch and Fujita. Their original publication represents a dramatic change of focus to incorporate consideration of log P after a decade of work unsuccessfully attempting to use the Hammett equation to explain the structure-activity relationships of plant growth regulators...
July 17, 2018: Journal of Computer-aided Molecular Design
Saveliy Belkin, Petras J Kundrotas, Ilya A Vakser
Modulating protein interaction pathways may lead to the cure of many diseases. Known protein-protein inhibitors bind to large pockets on the protein-protein interface. Such large pockets are detected also in the protein-protein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation...
July 12, 2018: Journal of Computer-aided Molecular Design
Jocelyn Sunseri, Jonathan E King, Paul G Francoeur, David Ryan Koes
We assess the ability of our convolutional neural network (CNN)-based scoring functions to perform several common tasks in the domain of drug discovery. These include correctly identifying ligand poses near and far from the true binding mode when given a set of reference receptors and classifying ligands as active or inactive using structural information. We use the CNN to re-score or refine poses generated using a conventional scoring function, Autodock Vina, and compare the performance of each of these methods to using the conventional scoring function alone...
July 10, 2018: Journal of Computer-aided Molecular Design
Matthew Habgood
Quantification of three-dimensional similarity between small molecules is a fundamental tool of rational drug design. However, there are no widely-adopted scoring approaches for comparing whole conformational ensembles between molecules. Such scores would be desirable for scenarios in which properties of a molecule have been measured (e.g. activity against a target) but the relevant three dimensional structure is not known. In this study, a set of three complementary ensemble comparison scores is proposed. These are the maximum similarity between any pair of conformations; the proportion of the whole set of the conformations that are matched to within a threshold 3D similarity score; and the average value over these matched conformations of the molecular shape descriptor 'σ-fct', introduced by Ballester et al...
July 9, 2018: Journal of Computer-aided Molecular Design
Hemavathy Nagarajan, Umashankar Vetrivel
Heparanase (HPSE) is an endo-β-D-glucuronidase that has diverse functions in mammals which includes cell survival, cell adhesion and cell migration. HPSE features both enzymatic and non-enzymatic functionalities in a pH dependent manner. Hence, in this study, an extensive molecular dynamics simulation, molecular docking, protein Angular dispersion analysis were performed for apo form and holo forms to understand its conformational changes at varied pH conditions. On comparative conformational analysis of apo and holo forms, it was inferred that the HSPE has undergone pH dependent structural changes, thereby affecting the binding of Heparan sulfate proteoglycan (HSPG)...
July 6, 2018: Journal of Computer-aided Molecular Design
Shibaji Ghosh, Kalyanashis Jana, Bishwajit Ganguly
The neutral oxime reactivator RS194B with a seven-membered ring has shown better efficacy towards the tabun-inhibited AChE than that of RS69N with a six-membered ring and RS41A with a five-membered ring. The difference in the efficacy of these reactivators has remained unexplored. We report here the origin of the difference of efficacy of these reactivators based on the conformational analysis, quantum chemical calculations and steered molecular dynamics (SMD) simulations. The conformational analysis using B3LYP/6-31G(d) level of theory revealed that RS41A and RS194B are more stable in gauche conformation due to the gauche effect (-N-C-C-N- bonds) whereas RS69N prefers anti-conformation...
July 6, 2018: Journal of Computer-aided Molecular Design
Marcela Vettorazzi, Cintia Menéndez, Lucas Gutiérrez, Sebastián Andujar, Gustavo Appignanesi, Ricardo D Enriz
We report here the results of two theoretical models to predict the inhibitory effect of inhibitors of sphingosine kinase 1 that stand on different computational basis. The active site of SphK1 is a complex system and the ligands under the study possess a significant conformational flexibility; therefore for our study we performed extended simulations and proper clusterization process. The two theoretical approaches used here, hydrogen bond dynamics propensity analysis and Quantum Theory of Atoms in Molecules (QTAIM) calculations, exhibit excellent correlations with the experimental data...
July 3, 2018: Journal of Computer-aided Molecular Design
Tomoyuki Miyao, Jürgen Bajorath
Shape similarity searching is a popular approach for ligand-based virtual screening on the basis of three-dimensional reference compounds. It is generally thought that well-defined experimentally determined binding modes of active reference compounds provide the best possible basis for shape searching. Herein, we show that experimental binding modes are not essential for successful shape similarity searching. Furthermore, we show that ensembles of analogs of X-ray ligands-in the absence of these ligands-further improve the search performance of single crystallographic reference compounds...
July 2, 2018: Journal of Computer-aided Molecular Design
Ann E Cleves, Ajay N Jain
We introduce the QuanSA method for inducing physically meaningful field-based models of ligand binding pockets based on structure-activity data alone. The method is closely related to the QMOD approach, substituting a learned scoring field for a pocket constructed of molecular fragments. The problem of mutual ligand alignment is addressed in a general way, and optimal model parameters and ligand poses are identified through multiple-instance machine learning. We provide algorithmic details along with performance results on sixteen structure-activity data sets covering many pharmaceutically relevant targets...
June 22, 2018: Journal of Computer-aided Molecular Design
Erick Martins Ratamero, Dom Bellini, Christopher G Dowson, Rudolf A Römer
The ability to precisely visualize the atomic geometry of the interactions between a drug and its protein target in structural models is critical in predicting the correct modifications in previously identified inhibitors to create more effective next generation drugs. It is currently common practice among medicinal chemists while attempting the above to access the information contained in three-dimensional structures by using two-dimensional projections, which can preclude disclosure of useful features. A more accessible and intuitive visualization of the three-dimensional configuration of the atomic geometry in the models can be achieved through the implementation of immersive virtual reality (VR)...
June 7, 2018: Journal of Computer-aided Molecular Design
Timothy Cholko, Wei Chen, Zhiye Tang, Chia-En A Chang
Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders...
May 8, 2018: Journal of Computer-aided Molecular Design
Mazen Y Hamed
Molecular dynamics and MM_GBSA energy calculations on various zinc finger proteins containing three and four fingers bound to their target DNA gave insights into the role of each finger in the DNA binding process as part of the protein structure. The wild type Zif 268 (PDB code: 1AAY) gave a ΔG value of - 76.1 (14) kcal/mol. Zinc fingers ZF1, ZF2 and ZF3 were mutated in one experiment and in another experiment one finger was cut and the rest of the protein was studied for binding. The ΔΔG values for the Zinc Finger protein with both ZF1 and ZF2 mutated was + 80 kcal/mol, while mutating only ZF1 the ΔΔG value was + 52 kcal/mol (relative to the wild type)...
May 3, 2018: Journal of Computer-aided Molecular Design
Sofja Tshepelevitsh, Kertu Hernits, Ivo Leito
Performance of COSMO-RS method as a tool for partition and distribution modeling in 20 solvent pairs-composed of neutral or acidic aqueous solution and organic solvents of different polarity, ranging from alcohols to toluene and hexane-was evaluated. Experimental partition/distribution data of lignin-related and drug-like compounds (neutral, acidic, moderately basic) were used as reference. Several aspects of partition modeling were addressed: accounting for mutual saturation of aqueous and organic phases, variability of systematic prediction errors across solvent pairs, taking solute ionization into account...
June 2018: Journal of Computer-aided Molecular Design
Thandokuhle Ntombela, Zeynab Fakhar, Collins U Ibeji, Thavendran Govender, Glenn E M Maguire, Gyanu Lamichhane, Hendrik G Kruger, Bahareh Honarparvar
Tuberculosis remains a dreadful disease that has claimed many human lives worldwide and elimination of the causative agent Mycobacterium tuberculosis also remains elusive. Multidrug-resistant TB is rapidly increasing worldwide; therefore, there is an urgent need for improving the current antibiotics and novel drug targets to successfully curb the TB burden. L,D-Transpeptidase 2 is an essential protein in Mtb that is responsible for virulence and growth during the chronic stage of the disease. Both D,D- and L,D-transpeptidases are inhibited concurrently to eradicate the bacterium...
June 2018: Journal of Computer-aided Molecular Design
Lu Lu, Hua Yu
Finding the new related candidate diseases for known drugs provides an effective method for fast-speed and low-risk drug development. However, experimental identification of drug-disease associations is expensive and time-consuming. This motivates the need for developing in silico computational methods that can infer true drug-disease pairs with high confidence. In this study, we presented a novel and powerful computational tool, DR2DI, for accurately uncovering the potential associations between drugs and diseases using high-dimensional and heterogeneous omics data as information sources...
May 2018: Journal of Computer-aided Molecular Design
Songling Ma, Jiwon Choi, Xuemei Jin, Hyun-Yi Kim, Ji-Hye Yun, Weontae Lee, Kang-Yell Choi, Kyoung Tai No
The Wnt/β-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl-CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD)...
May 2018: Journal of Computer-aided Molecular Design
Sankalp Jain, Eleni Kotsampasakou, Gerhard F Ecker
Cheminformatics datasets used in classification problems, especially those related to biological or physicochemical properties, are often imbalanced. This presents a major challenge in development of in silico prediction models, as the traditional machine learning algorithms are known to work best on balanced datasets. The class imbalance introduces a bias in the performance of these algorithms due to their preference towards the majority class. Here, we present a comparison of the performance of seven different meta-classifiers for their ability to handle imbalanced datasets, whereby Random Forest is used as base-classifier...
May 2018: Journal of Computer-aided Molecular Design
Francesca Cardamone, Mattia Falconi, Alessandro Desideri
Aicardi-Goutières syndrome, a rare genetic disorder characterized by calcification of basal ganglia, results in psychomotor delays and epilepsy states from the early months of children life. This disease is caused by mutations in seven different genes encoding proteins implicated in the metabolism of nucleic acids, including SAMHD1. Twenty SAMHD1 gene variants have been discovered and in this work, a structural characterization of the SAMHD1 Aicardi-Goutières Arg145Gln mutant is reported by classical molecular dynamics simulation...
May 2018: Journal of Computer-aided Molecular Design
Érica C M Nascimento, Mónica Oliva, Juan Andrés
In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters highlight the importance of the stereochemistry of huprines in AChE inhibition. Binding isotope effects are calculated to unravel the interactions between ligands and the gorge of AChE. New chemical insights are provided to explain and rationalize the experimental results...
May 2018: Journal of Computer-aided Molecular Design
Luan Carvalho Martins, Pedro Henrique Monteiro Torres, Renata Barbosa de Oliveira, Pedro Geraldo Pascutti, Elio A Cino, Rafaela Salgado Ferreira
Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC50  = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization...
May 2018: Journal of Computer-aided Molecular Design
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