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Journal of Chemical Information and Modeling

Jing Xing, Wenchao Lu, Rongfeng Liu, Yulan Wang, Yiqian Xie, Hao Zhang, Zhe Shi, Hao Jiang, Yu-Chih Liu, Kaixian Chen, Hualiang Jiang, Cheng Luo, Mingyue Zheng
Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential anti-resistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4...
June 21, 2017: Journal of Chemical Information and Modeling
Giulio Vistoli, Angelica Mazzolari, Bernard Testa, Alessandro Pedretti
Docking simulations are very popular approaches able to assess the capacity of a given ligand to interact with a target. Docking simulations are usually focused on a single best complex even though many studies showed that ligands retain a significant mobility within a binding pocket by assuming different binding modes all of which may contribute to the monitored ligand affinity. The present study describes an innovative concept, the binding space, which allows an exploration of the ligand mobility within the binding pocket by simultaneously considering several ligand poses as generated by docking simulations...
June 20, 2017: Journal of Chemical Information and Modeling
Menyhárt-Botond Sárosi, Wilma Neumann, Terry P Lybrand, Evamarie Hey-Hawkins
Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase 2 (COX 2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data...
June 20, 2017: Journal of Chemical Information and Modeling
Jiangming Sun, Lars Carlsson, Ernst Ahlberg, Ulf Norinder, Ola Engkvist, Hongming Chen
Conformal prediction has been proposed as a more rigorous way to define prediction confidence compared to other application domain concepts that have earlier been used for QSAR modelling. One main advantage of such a method is that it provides a prediction region potentially with multiple predicted labels, which contrasts to the single valued (regression) or single label (classification) output predictions by standard QSAR modelling algorithms. Standard conformal prediction might not be suitable for imbalanced datasets...
June 19, 2017: Journal of Chemical Information and Modeling
Suqing Zheng, Shaofang Xu, Guitao Wang, Qing Tang, Xiaonan Jiang, Zhanting Li, Yong Xu, Renxiao Wang, Fu Lin
In this work, we tentatively propose that the hydrogen-bonding strength EHB (referring to the minimal hydrogen-bonding energy) and its corresponding hydrogen-bond (HB) distance (referring to the optimal HB distance dHB) for simple mono-HB systems have an exponential relationship on the basis of MP2 and DFT computational results. We take a step further and propose that the hydrogen-bonding indices of the donor (Idonor) and acceptor (Iacceptor), reflecting their intrinsic contributions to hydrogen-bonding strength, also have an exponential relation with the hypothetical effective hydrogen-bond radii of the donor (rdonor) and acceptor (racceptor), respectively...
June 16, 2017: Journal of Chemical Information and Modeling
Stefan Güssregen, Hans Matter, Gerhard Hessler, Evanthia Lionta, Jochen Heil, Stefan M Kast
Water molecules play an essential role for mediating interactions between ligands and protein binding sites. Displacement of specific water molecules can favorably modulate the free energy of binding of protein-ligand complexes. Here, the nature of water interactions in protein binding sites is investigated by 3D RISM (three-dimensional reference interaction site model) integral equation theory to understand and exploit local thermodynamic features of water molecules by ranking their possible displacement in structure-based design...
June 16, 2017: Journal of Chemical Information and Modeling
Stefano Motta, Laura Bonati
Protein dynamics play a critical role in ligand binding, and different models have been proposed to explain the relationships between protein motion and molecular recognition. Here, we present a study of ligand-binding processes associated with large conformational changes of a protein to elucidate the critical choices in ensemble-docking approaches for effective prediction of the binding geometry. Two study cases were selected in which binding involves different protein motions and intermolecular interactions and, accordingly, conformational selection and induced-fit mechanisms play different roles: binding of multiple ligands to the acetylcholine binding protein and highly specific binding of D-allose to the allose binding protein...
June 15, 2017: Journal of Chemical Information and Modeling
Natalia Khuri, Arik A Zur, Matthias B Wittwer, Lawrence Lin, Sook Wah Yee, Andrej Sali, Kathleen M Giacomini
Human organic anion transporters (OATPs) are vital for the uptake and efflux of drugs and endogenous compounds. Current identification of inhibitors of these transporters is based on experimental screening. Virtual screening remains a challenge due to a lack of experimental three-dimensional protein structures. Here, we describe a workflow to identify inhibitors of the OATP2B1 transporter in the DrugBank library of over 5,000 drugs and druglike molecules. OATP member 2B1 transporter is highly expressed in the intestine, where it participates in oral absorption of drugs...
June 15, 2017: Journal of Chemical Information and Modeling
Yunhui Ge, Brandon L Kier, Niels H Andersen, Vincent Alvin Voelz
Molecular simulation has been used to model the detailed folding properties of peptides, yet prospective computational peptide design by such approaches remains challenging and non-trivial. To test the accuracy of simulation-based hairpin design, we characterized the folding properties of a series of so-called β-capped hairpin peptides designed to mimic a conserved hairpin of LapD, a bacterial intracellular signaling protein, both experimentally by NMR and computationally by implicit-solvent replica-exchange molecular dynamics (REMD) for three different AMBER force fields (ff96, ff99sb-ildn and ff99sb-ildn-nmr)...
June 14, 2017: Journal of Chemical Information and Modeling
Wei Xiao, Zenghui He, Meijian Sun, Shiliang Li, Honglin Li
Water molecules play a crucial role in biomolecular associations by mediating a hydrogen bond network or filling spaces with van der Waals interactions. Although current drug design technologies have taken water molecule interactions into account, their applications are still limited to their reliance on either excessive computer resources or a particular potential energy model. Here, we introduce a statistical method that is based on experimentally-determined water molecules in the binding sites of high-resolution X-ray crystal structures to predict the potential hydration sites in the binding sites of a crystal structures of interest...
June 12, 2017: Journal of Chemical Information and Modeling
KwangHyok Jong, Luca Grisanti, Ali A Hassanali
We study the conformational landscape of the C-terminal fragment of the Amyloid protein Aβ30-35 in water using well-tempered metadynamics simulations and find that it resembles an intrinsically disordered protein. The conformational fluctuations of the protein are facilitated by a collective reorganization of both protein and water hydrogen bond networks, combined with electrostatic interactions between termini as well as hydrophobic interactions of the side chains. The stabilization of hydrophobic interactions in one of the conformers involves a collective collapse of the sidechains along with a squeeze out of water sandwiched in between...
June 12, 2017: Journal of Chemical Information and Modeling
Fude Sun, Long Chen, Peng Wei, Mengya Chai, Xiufang Ding, Lida Xu, Shi-Zhong Luo
The lipid raft microenvironment is implicated in the generation of the pathological amyloid-β (Aβ) species in amyloid precursor protein (APP) that is associated with neurodegenerative diseases. Evidence shows that APP forms a transmembrane homodimer with changeable structures as a function of the membrane compositions. However, the molecular responsibility of the dimerization and structural alteration for the amyloidogenic process in segregated membranes remains largely unclear. Here, we performed multiple coarse grained (CG) simulations to explore the behavioral preference of the transmembrane domain of APP (called C99) that is affected by the lipid raft microenvironment...
June 9, 2017: Journal of Chemical Information and Modeling
Gerard Martinez-Rosell, Toni Giorgino, Gianni De Fabritiis
Protein preparation is a critical step in molecular simulations consisting in refining a protein PDB structure by assigning titration states and optimizing the hydrogen bonding network. In this application note, we describe ProteinPrepare, a web application designed to interactively support the preparation of protein structures. Users can upload a PDB file, choose the solvent pH value, and inspect the resulting protonated residues and H-bonding network within a 3D web interface. Protonation states are suggested automatically, but can be manually changed using the visual aid of the hydrogen bond network...
June 8, 2017: Journal of Chemical Information and Modeling
Stephanie Jephthah, João Henriques, Carolina Cragnell, Sumant Puri, Mira Edgerton, Marie Skepö
Histatin 5 (Hst5) is a naturally occurring antimicrobial peptide that acts as the first line of defense against oral candidiasis. It has been shown that conjugation of the active Hst5 fragment, Hst54-15, and the polyamine spermidine (Spd) improves the candidacidal effect. Knowledge about the structure of these conjugates is, however, very limited. Thus, the aim of this study was to characterize the structural properties of the Hst54-15-Spd conjugates by performing atomistic molecular dynamics simulations in combination with small-angle X-ray scattering...
June 6, 2017: Journal of Chemical Information and Modeling
Piero Procacci
We present PrimaDORAC, a simple and freely accessible web interface for generating the topology and the parameter files of organic or drug molecules, to be used in molecular mechanics or molecular dynamics calculations. The interface relies on our in-house FORTRAN90 parser, working on the recently released Generalized Amber Force Field parameter set (GAFF2). AM1/BCC charges are computed using the Public Domain MOPAC7 program and the bond charge corrections (BCC) reported in Ref. Jakalian et al, J Comp Chem, 2002, 23, 1623-1641...
June 6, 2017: Journal of Chemical Information and Modeling
Shubhadip Das, Sandip Paul
We perform classical molecular dynamics simulations of sparingly soluble drug gliclazide (GLC) and hydrotrope p-toluidinium chloride (PTOL) in water with a regime of PTOL concentrations. Our results demonstrate that PTOL starts to self-aggregate above its minimum hydrotrope concentration (MHC). Further, these PTOL aggregates create a mixed micellar-like framework in which the hydrophobic small tail part of most of the PTOL molecules direct toward the inside, whereas in order to make favorable contact with water molecules its hydrophilic ammonium group points outward...
June 1, 2017: Journal of Chemical Information and Modeling
Jie Xia, Jui-Hua Hsieh, Huabin Hu, Song Wu, Xiang Simon Wang
Structure-based virtual screening (SBVS) has become an indispensable technique for hit identification at the early stage of drug discovery. However, the accuracy of current scoring functions is not high enough to confer success to every target and thus remains to be improved. Previously, we had developed binary pose filters (PFs) using knowledge derived from the protein-ligand interface of a single X-ray structure of a specific target. This novel approach had been validated as an effective way to improve ligand enrichment...
June 1, 2017: Journal of Chemical Information and Modeling
Luca Codutti, Manuela Grimaldi, Teresa Carlomagno
Phosphodiesterases (PDE) hydrolyze both cyclic AMP and GMP (cAMP/cGMP) and are responsible for the regulation of their levels in a multitude of cellular functions. PDE10A is expressed in the brain and is a validated target for both schizophrenia and Huntington disease. Here, we address the identification of novel chemical scaffolds that may bind PDE10A via structure-based drug design. For this task, we use INPHARMA, an NMR-based method that measures protein-mediated interligand NOEs between pairs of weakly, competitively binding ligands...
May 31, 2017: Journal of Chemical Information and Modeling
Weilin Zhang, Jianfeng Pei, Luhua Lai
Targeted covalent compounds or drugs have good potency as they can bind to a specific target for a long time with low doses. Most currently known covalent ligands were discovered by chance or by modifying existing noncovalent compounds to make them covalently attached to a nearby reactive residue. Computational methods for novel covalent ligand binding prediction are highly demanded. We performed statistical analysis on protein complexes with covalent ligands attached to cysteine residues. We found that covalent modified cysteine residues have unique features compared to those not attached to covalent ligands, including lower pKa, higher exposure, and higher ligand binding affinity...
May 30, 2017: Journal of Chemical Information and Modeling
Xiuquan Du, Shiwei Sun, Changlin Hu, Yu Yao, Yuanting Yan, Yanping Zhang
The complex language of eukaryotic gene expression remains incompletely understood. Despite the importance suggested by many proteins variants statistically associated with human disease, nearly all such variants have unknown mechanisms, for example, protein-protein interactions (PPIs). In this study, we address this challenge using a recent machine learning advance-deep neural networks (DNNs). We aim at improving the performance of PPIs prediction and propose a method called DeepPPI (Deep neural networks for Protein-Protein Interactions prediction), which employs deep neural networks to learn effectively the representations of proteins from common protein descriptors...
May 26, 2017: Journal of Chemical Information and Modeling
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