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Journal of Computer-aided Molecular Design

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https://www.readbyqxmd.com/read/28631130/new-insights-into-human-farnesyl-pyrophosphate-synthase-inhibition-by-second-generation-bisphosphonate-drugs
#1
D Fernández, R Ramis, J Ortega-Castro, R Casasnovas, B Vilanova, J Frau
Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC50 values...
June 19, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28624971/excelautomat-a-tool-for-systematic-processing-of-files-as-applied-to-quantum-chemical-calculations
#2
Jalal Z A Laloo, Nassirah Laloo, Lydia Rhyman, Ponnadurai Ramasami
The processing of the input and output files of quantum chemical calculations often necessitates a spreadsheet as a key component of the workflow. Spreadsheet packages with a built-in programming language editor can automate the steps involved and thus provide a direct link between processing files and the spreadsheet. This helps to reduce user-interventions as well as the need to switch between different programs to carry out each step. The ExcelAutomat tool is the implementation of this method in Microsoft Excel (MS Excel) using the default Visual Basic for Application (VBA) programming language...
June 17, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28623487/multiple-receptor-ligand-based-pharmacophore-modeling-and-molecular-docking-to-screen-the-selective-inhibitors-of-matrix-metalloproteinase-9-from-natural-products
#3
Qi Gao, Yijun Wang, Jiaying Hou, Qizheng Yao, Ji Zhang
Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors...
June 16, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28623486/galaxydock-bp2-score-a-hybrid-scoring-function-for-accurate-protein-ligand-docking
#4
Minkyung Baek, Woong-Hee Shin, Hwan Won Chung, Chaok Seok
Protein-ligand docking is a useful tool for providing atomic-level understanding of protein functions in nature and design principles for artificial ligands or proteins with desired properties. The ability to identify the true binding pose of a ligand to a target protein among numerous possible candidate poses is an essential requirement for successful protein-ligand docking. Many previously developed docking scoring functions were trained to reproduce experimental binding affinities and were also used for scoring binding poses...
June 16, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28623485/is-scaffold-hopping-a-reliable-indicator-for-the-ability-of-computational-methods-to-identify-structurally-diverse-active-compounds
#5
Dilyana Dimova, Jürgen Bajorath
Computational scaffold hopping aims to identify core structure replacements in active compounds. To evaluate scaffold hopping potential from a principal point of view, regardless of the computational methods that are applied, a global analysis of conventional scaffolds in analog series from compound activity classes was carried out. The majority of analog series was found to contain multiple scaffolds, thus enabling the detection of intra-series scaffold hops among closely related compounds. More than 1000 activity classes were found to contain increasing proportions of multi-scaffold analog series...
June 16, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28597356/structural-insight-into-the-role-of-gln293met-mutation-on-the-peloruside-a-laulimalide-association-with-%C3%AE-%C3%AE-tubulin-from-molecular-dynamics-simulations-binding-free-energy-calculations-and-weak-interactions-analysis
#6
Matías A Zúñiga, Joel B Alderete, Gonzalo A Jaña, Verónica A Jiménez
Peloruside A (PLA) and Laulimalide (LAU) are novel microtubule-stabilizing agents with promising properties against different cancer types. These ligands share a non-taxoid binding site at the outer surface of β-tubulin and promote microtubule stabilization by bridging two adjacent αβ-tubulin dimers from parallel protofilaments. Recent site-directed mutagenesis experiments confirmed the existence of a unique β-tubulin site mutation (Gln293Met) that specifically increased the activity of PLA and caused resistance to LAU, without affecting the stability of microtubules in the absence of the ligands...
June 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28573347/molalign-an-algorithm-for-aligning-multiple-small-molecules
#7
Shek Ling Chan
In small molecule drug discovery projects, the receptor structure is not always available. In such cases it is enormously useful to be able to align known ligands in the way they bind in the receptor. Here we shall present an algorithm for the alignment of multiple small molecule ligands. This algorithm takes pre-generated conformers as input, and proposes aligned assemblies of the ligands. The algorithm consists of two stages: the first stage is to perform alignments for each pair of ligands, the second stage makes use of the results from the first stage to build up multiple ligand alignment assemblies using a novel iterative procedure...
June 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28573346/a-critical-assessment-of-finite-element-modeling-approach-for-protein-dynamics
#8
Giseok Yun, Jaehoon Kim, Do-Nyun Kim
Finite element (FE) modeling approach has emerged as an efficient way of calculating the dynamic properties of supramolecular protein structures and their complexes. Its efficiency mainly stems from the fact that the complexity of three-dimensional shape of a molecular surface dominates the computational cost rather than the molecular size or the number of atoms. However, no critical evaluation of the method has been made yet particularly for its sensitivity to the parameters used in model construction. Here, we make a close investigation on the effect of FE model parameters by analyzing 135 representative protein structures whose normal modes calculated using all-atom normal mode analysis are publicly accessible online...
June 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28551817/discovery-of-novel-inhibitors-for-leishmania-nucleoside-diphosphatase-kinase-ndk-based-on-its-structural-and-functional-characterization
#9
Arjun K Mishra, Nidhi Singh, Pragati Agnihotri, Shikha Mishra, Saurabh P Singh, Bala K Kolli, Kwang Poo Chang, Amogh A Sahasrabuddhe, M I Siddiqi, J Venkatesh Pratap
Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis...
May 27, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28550607/dft-based-prediction-of-reactivity-of-short-chain-alcohol-dehydrogenase
#10
I Stawoska, A Dudzik, M Wasylewski, M Jemioła-Rzemińska, A Skoczowski, K Strzałka, M Szaleniec
The reaction mechanism of ketone reduction by short chain dehydrogenase/reductase, (S)-1-phenylethanol dehydrogenase from Aromatoleum aromaticum, was studied with DFT methods using cluster model approach. The characteristics of the hydride transfer process were investigated based on reaction of acetophenone and its eight structural analogues. The results confirmed previously suggested concomitant transfer of hydride from NADH to carbonyl C atom of the substrate with proton transfer from Tyr to carbonyl O atom...
May 26, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28534194/assessing-protein-ligand-binding-modes-with-computational-tools-the-case-of-pde4b
#11
Gülşah Çifci, Viktorya Aviyente, E Demet Akten, Gerald Monard
In a first step in the discovery of novel potent inhibitor structures for the PDE4B family with limited side effects, we present a protocol to rank newly designed molecules through the estimation of their IC[Formula: see text] values. Our protocol is based on reproducing the linear relationship between the logarithm of experimental IC[Formula: see text] values [[Formula: see text](IC[Formula: see text])] and their calculated binding free energies ([Formula: see text]). From 13 known PDE4B inhibitors, we show here that (1) binding free energies obtained after a docking process by AutoDock are not accurate enough to reproduce this linear relationship; (2) MM-GB/SA post-processing of molecular dynamics (MD) trajectories of the top ranked AutoDock pose improves the linear relationship; (3) by taking into account all representative structures obtained by AutoDock and by averaging MM-GB/SA computations on a series of 40 independent MD trajectories, a linear relationship between [Formula: see text](IC[Formula: see text]) and the lowest [Formula: see text] is achieved with [Formula: see text]...
May 22, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28534193/antagonist-perturbation-mechanism-for-activation-function-2-fixed-motifs-active-conformation-and-docking-mode-of-retinoid-x-receptor-antagonists
#12
Motonori Tsuji
HX531, which contains a dibenzodiazepine skeleton, is one of the first retinoid X receptor (RXR) antagonists. Functioning via RXR-PPARγ heterodimer, this compound is receiving a lot of attention as a therapeutic drug candidate for diabetic disease controlling differentiation of adipose tissue. However, the active conformation of HX531 for RXRs is not well established. In the present study, quantum mechanics calculations and molecular mechanical docking simulations were carried out to precisely study the docking mode of HX531 with the human RXRα ligand-binding domain, as well as to provide a new approach to drug design using a structure-based perspective...
May 22, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28527154/structure-based-classification-for-bile-salt-export-pump-bsep-inhibitors-using-comparative-structural-modeling-of-human-bsep
#13
Sankalp Jain, Melanie Grandits, Lars Richter, Gerhard F Ecker
The bile salt export pump (BSEP) actively transports conjugated monovalent bile acids from the hepatocytes into the bile. This facilitates the formation of micelles and promotes digestion and absorption of dietary fat. Inhibition of BSEP leads to decreased bile flow and accumulation of cytotoxic bile salts in the liver. A number of compounds have been identified to interact with BSEP, which results in drug-induced cholestasis or liver injury. Therefore, in silico approaches for flagging compounds as potential BSEP inhibitors would be of high value in the early stage of the drug discovery pipeline...
May 19, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28374255/qsar-modeling-and-chemical-space-analysis-of-antimalarial-compounds
#14
Pavel Sidorov, Birgit Viira, Elisabeth Davioud-Charvet, Uko Maran, Gilles Marcou, Dragos Horvath, Alexandre Varnek
Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models...
April 3, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28364251/allosteric-modulation-model-of-the-mu-opioid-receptor-by-herkinorin-a-potent-not-alkaloidal-agonist
#15
A F Marmolejo-Valencia, K Martínez-Mayorga
Modulation of opioid receptors is the primary choice for pain management and structural information studies have gained new horizons with the recently available X-ray crystal structures. Herkinorin is one of the most remarkable salvinorin A derivative with high affinity for the mu opioid receptor, moderate selectivity and lack of nitrogen atoms on its structure. Surprisingly, binding models for herkinorin are lacking. In this work, we explore binding models of herkinorin using automated docking, molecular dynamics simulations, free energy calculations and available experimental information...
March 31, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28365882/proteus-a-random-forest-classifier-to-predict-disorder-to-order-transitioning-binding-regions-in-intrinsically-disordered-proteins
#16
Sankar Basu, Fredrik Söderquist, Björn Wallner
The focus of the computational structural biology community has taken a dramatic shift over the past one-and-a-half decades from the classical protein structure prediction problem to the possible understanding of intrinsically disordered proteins (IDP) or proteins containing regions of disorder (IDPR). The current interest lies in the unraveling of a disorder-to-order transitioning code embedded in the amino acid sequences of IDPs/IDPRs. Disordered proteins are characterized by an enormous amount of structural plasticity which makes them promiscuous in binding to different partners, multi-functional in cellular activity and atypical in folding energy landscapes resembling partially folded molten globules...
May 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28289981/forcegen-3d-structure-and-conformer-generation-from-small-lead-like-molecules-to-macrocyclic-drugs
#17
Ann E Cleves, Ajay N Jain
We introduce the ForceGen method for 3D structure generation and conformer elaboration of drug-like small molecules. ForceGen is novel, avoiding use of distance geometry, molecular templates, or simulation-oriented stochastic sampling. The method is primarily driven by the molecular force field, implemented using an extension of MMFF94s and a partial charge estimator based on electronegativity-equalization. The force field is coupled to algorithms for direct sampling of realistic physical movements made by small molecules...
May 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28321532/as-rigid-as-possible-molecular-interpolation-paths
#18
Minh Khoa Nguyen, Léonard Jaillet, Stéphane Redon
This paper proposes a new method to generate interpolation paths between two given molecular conformations. It relies on the As-Rigid-As-Possible (ARAP) paradigm used in Computer Graphics to manipulate complex meshes while preserving their essential structural characteristics. The adaptation of ARAP approaches to the case of molecular systems is presented in this contribution. Experiments conducted on a large set of benchmarks show how such a strategy can efficiently compute relevant interpolation paths with large conformational rearrangements...
April 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315995/ligand-based-virtual-screening-under-partial-shape-constraints
#19
Mathias M von Behren, Matthias Rarey
Ligand-based virtual screening has proven to be a viable technology during the search for new lead structures in drug discovery. Despite the rapidly increasing number of published methods, meaningful shape matching as well as ligand and target flexibility still remain open challenges. In this work, we analyze the influence of knowledge-based sterical constraints on the performance of the recently published ligand-based virtual screening method mRAISE. We introduce the concept of partial shape matching enabling a more differentiated view on chemical structure...
April 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28281211/bayesian-molecular-design-with-a-chemical-language-model
#20
Hisaki Ikebata, Kenta Hongo, Tetsu Isomura, Ryo Maezono, Ryo Yoshida
The aim of computational molecular design is the identification of promising hypothetical molecules with a predefined set of desired properties. We address the issue of accelerating the material discovery with state-of-the-art machine learning techniques. The method involves two different types of prediction; the forward and backward predictions. The objective of the forward prediction is to create a set of machine learning models on various properties of a given molecule. Inverting the trained forward models through Bayes' law, we derive a posterior distribution for the backward prediction, which is conditioned by a desired property requirement...
April 2017: Journal of Computer-aided Molecular Design
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