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Journal of Computer-aided Molecular Design

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https://www.readbyqxmd.com/read/28342136/molecular-basis-of-p450-oletje-an-investigation-of-substrate-binding-mechanism-and-major-pathways
#1
Juan Du, Lin Liu, Li Zhong Guo, Xiao Jun Yao, Jian Ming Yang
Cytochrome P450 OleTJE has attracted much attention for its ability to catalyze the decarboxylation of long chain fatty acids to generate alkenes, which are not only biofuel molecule, but also can be used broadly for making lubricants, polymers and detergents. In this study, the molecular basis of the binding mechanism of P450 OleTJE for arachidic acid, myristic acid, and caprylic acid was investigated by utilizing conventional molecular dynamics simulation and binding free energy calculations. Moreover, random acceleration molecular dynamics (RAMD) simulations were performed to uncover the most probable access/egress channels for different fatty acids...
March 25, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28321532/as-rigid-as-possible-molecular-interpolation-paths
#2
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...
March 20, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315995/ligand-based-virtual-screening-under-partial-shape-constraints
#3
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...
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315994/urgency-and-austerity-as-drivers-of-success
#4
Terry R Stouch
This piece describes the approach by which even a small CADD (Computer-Aided Drug Design) group with limited resources and limited time can achieve substantial success given short budgets and the compressed, urgent environment of a biotech. Some comparisons are made with CADD operations in big pharma.
March 18, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28315993/a-cadd-alog-of-strategies-in-pharma
#5
EDITORIAL
Wendy A Warr
A special issue on computer-aided drug design (CADD) strategies in pharma discusses how CADD groups in different environments work. Perspectives were collected from authors in 11 organizations: four big pharmaceutical companies, one major biotechnology company, one smaller biotech, one private pharmaceutical company, two contract research organizations (CROs), one university, and one that spans the breadth of big pharmaceutical companies and one smaller biotech.
March 18, 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
#6
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...
March 13, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28281211/bayesian-molecular-design-with-a-chemical-language-model
#7
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...
March 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28251415/a-molecular-dynamics-simulation-study-decodes-the-early-stage-of-the-disassembly-process-abolishing-the-human-samhd1-function
#8
Francesca Cardamone, Federico Iacovelli, Giovanni Chillemi, Mattia Falconi, Alessandro Desideri
The human sterile alpha motif SAM and HD domain-containing protein 1 (SAMHD1) restricts in non-cycling cells type the infection of a large range of retroviruses including HIV-1, reducing the intracellular pool concentration of deoxynucleoside triphosphates (dNTPs) required for the reverse transcription of the viral genome. The enzyme is in equilibrium between different forms depending on bound cofactors and substrate. In this work, two SAMHD1 three-dimensional models have been investigated through classical molecular dynamics simulation, to define the role of cofactors and metal ions in the association of the tetrameric active form...
March 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28220440/quantum-probability-ranking-principle-for-ligand-based-virtual-screening
#9
Mohammed Mumtaz Al-Dabbagh, Naomie Salim, Mubarak Himmat, Ali Ahmed, Faisal Saeed
Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP)...
February 20, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28190218/drude-polarizable-force-field-for-aliphatic-ketones-and-aldehydes-and-their-associated-acyclic-carbohydrates
#10
Meagan C Small, Asaminew H Aytenfisu, Fang-Yu Lin, Xibing He, Alexander D MacKerell
The majority of computer simulations exploring biomolecular function employ Class I additive force fields (FF), which do not treat polarization explicitly. Accordingly, much effort has been made into developing models that go beyond the additive approximation. Development and optimization of the Drude polarizable FF has yielded parameters for selected lipids, proteins, DNA and a limited number of carbohydrates. The work presented here details parametrization of aliphatic aldehydes and ketones (viz. acetaldehyde, propionaldehyde, butaryaldehyde, isobutaryaldehyde, acetone, and butanone) as well as their associated acyclic sugars (D-allose and D-psicose)...
February 11, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28155089/predicting-dpp-iv-inhibitors-with-machine-learning-approaches
#11
Jie Cai, Chanjuan Li, Zhihong Liu, Jiewen Du, Jiming Ye, Qiong Gu, Jun Xu
Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects...
February 2, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28132112/combining-mosced-with-molecular-simulation-free-energy-calculations-or-electronic-structure-calculations-to-develop-an-efficient-tool-for-solvent-formulation-and-selection
#12
Courtney E Cox, Jeremy R Phifer, Larissa Ferreira da Silva, Gabriel Gonçalves Nogueira, Ryan T Ley, Elizabeth J O'Loughlin, Ana Karolyne Pereira Barbosa, Brett T Rygelski, Andrew S Paluch
Solubility parameter based methods have long been a valuable tool for solvent formulation and selection. Of these methods, the MOdified Separation of Cohesive Energy Density (MOSCED) has recently been shown to correlate well the equilibrium solubility of multifunctional non-electrolyte solids. However, before it can be applied to a novel solute, a limited amount of reference solubility data is required to regress the necessary MOSCED parameters. Here we demonstrate for the solutes methylparaben, ethylparaben, propylparaben, butylparaben, lidocaine and ephedrine how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here the SMD or SM8 solvation model, can instead be used to generate the necessary reference data, resulting in a predictive flavor of MOSCED...
January 28, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28102461/rnahelix-computational-modeling-of-nucleic-acid-structures-with-watson-crick-and-non-canonical-base-pairs
#13
Dhananjay Bhattacharyya, Sukanya Halder, Sankar Basu, Debasish Mukherjee, Prasun Kumar, Manju Bansal
Comprehensive analyses of structural features of non-canonical base pairs within a nucleic acid double helix are limited by the availability of a small number of three dimensional structures. Therefore, a procedure for model building of double helices containing any given nucleotide sequence and base pairing information, either canonical or non-canonical, is seriously needed. Here we describe a program RNAHelix, which is an updated version of our widely used software, NUCGEN. The program can regenerate duplexes using the dinucleotide step and base pair orientation parameters for a given double helical DNA or RNA sequence with defined Watson-Crick or non-Watson-Crick base pairs...
January 19, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28074360/exploring-the-stability-of-ligand-binding-modes-to-proteins-by-molecular-dynamics-simulations
#14
Kai Liu, Etsurou Watanabe, Hironori Kokubo
The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed the stability of various ligand poses under molecular dynamics (MD) simulation. First, a data set of 120 complexes was built based on the typical physicochemical properties of drug-like ligands. Three potential binding poses (one correct pose and two decoys) were selected for each ligand from self-docking in addition to the experimental pose...
January 10, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28070730/cadd-medicine-design-is-the-potion-that-can-cure-my-disease
#15
Eric S Manas, Darren V S Green
The acronym "CADD" is often used interchangeably to refer to "Computer Aided Drug Discovery" and "Computer Aided Drug Design". While the former definition implies the use of a computer to impact one or more aspects of discovering a drug, in this paper we contend that computational chemists are most effective when they enable teams to apply true design principles as they strive to create medicines to treat human disease. We argue that teams must bring to bear multiple sub-disciplines of computational chemistry in an integrated manner in order to utilize these principles to address the multi-objective nature of the drug discovery problem...
January 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28063067/dockingapp-a-user-friendly-interface-for-facilitated-docking-simulations-with-autodock-vina
#16
Elena Di Muzio, Daniele Toti, Fabio Polticelli
Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking...
January 6, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28054187/the-influence-of-hydrogen-bonding-on-partition-coefficients
#17
Nádia Melo Borges, Peter W Kenny, Carlos A Montanari, Igor M Prokopczyk, Jean F R Ribeiro, Josmar R Rocha, Geraldo Rodrigues Sartori
This Perspective explores how consideration of hydrogen bonding can be used to both predict and better understand partition coefficients. It is shown how polarity of both compounds and substructures can be estimated from measured alkane/water partition coefficients. When polarity is defined in this manner, hydrogen bond donors are typically less polar than hydrogen bond acceptors. Analysis of alkane/water partition coefficients in conjunction with molecular electrostatic potential calculations suggests that aromatic chloro substituents may be less lipophilic than is generally believed and that some of the effect of chloro-substitution stems from making the aromatic π-cloud less available to hydrogen bond donors...
January 4, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27677749/absolute-binding-free-energy-calculations-of-cbclip-host-guest-systems-in-the-sampl5-blind-challenge
#18
Juyong Lee, Florentina Tofoleanu, Frank C Pickard, Gerhard König, Jing Huang, Ana Damjanović, Minkyung Baek, Chaok Seok, Bernard R Brooks
Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett's acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method...
January 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27658802/overview-of-the-sampl5-host-guest-challenge-are-we-doing-better
#19
Jian Yin, Niel M Henriksen, David R Slochower, Michael R Shirts, Michael W Chiu, David L Mobley, Michael K Gilson
The ability to computationally predict protein-small molecule binding affinities with high accuracy would accelerate drug discovery and reduce its cost by eliminating rounds of trial-and-error synthesis and experimental evaluation of candidate ligands. As academic and industrial groups work toward this capability, there is an ongoing need for datasets that can be used to rigorously test new computational methods. Although protein-ligand data are clearly important for this purpose, their size and complexity make it difficult to obtain well-converged results and to troubleshoot computational methods...
January 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27638809/the-sampl5-host-guest-challenge-computing-binding-free-energies-and%C3%A2-enthalpies-from-explicit-solvent-simulations-by-the-attach-pull-release-apr-method
#20
Jian Yin, Niel M Henriksen, David R Slochower, Michael K Gilson
The absolute binding free energies and binding enthalpies of twelve host-guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R(2)) of 0...
January 2017: Journal of Computer-aided Molecular Design
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