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Journal of Computer-aided Molecular Design

Hugo de Almeida, Vincent Leroux, Flávia Nader Motta, Philippe Grellier, Bernard Maigret, Jaime M Santana, Izabela Marques Dourado Bastos
We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a "jaw opening" gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays...
October 21, 2016: Journal of Computer-aided Molecular Design
Ma'mon M Hatmal, Shadi Jaber, Mutasem O Taha
Ligand-based pharmacophore modeling require relatively long lists of active compounds, while a pharmacophore based on a single ligand-receptor crystallographic structure is often promiscuous. These problems prompted us to combine molecular dynamics (MD) simulation with ligand-receptor contacts analysis as means to develop valid pharmacophore model(s). The particular ligand-receptor complex is allowed to perturb over a few nano-seconds using MD simulation. Subsequently, ligand-receptor contact points (≤2.5 Å) are identified...
October 8, 2016: Journal of Computer-aided Molecular Design
Sergei Grudinin, Maria Kadukova, Andreas Eisenbarth, Simon Marillet, Frédéric Cazals
The 2015 D3R Grand Challenge provided an opportunity to test our new model for the binding free energy of small molecules, as well as to assess our protocol to predict binding poses for protein-ligand complexes. Our pose predictions were ranked 3-9 for the HSP90 dataset, depending on the assessment metric. For the MAP4K dataset the ranks are very dispersed and equal to 2-35, depending on the assessment metric, which does not provide any insight into the accuracy of the method. The main success of our pose prediction protocol was the re-scoring stage using the recently developed Convex-PL potential...
October 7, 2016: Journal of Computer-aided Molecular Design
Ariën S Rustenburg, Justin Dancer, Baiwei Lin, Jianwen A Feng, Daniel F Ortwine, David L Mobley, John D Chodera
Small molecule distribution coefficients between immiscible nonaqueuous and aqueous phases-such as cyclohexane and water-measure the degree to which small molecules prefer one phase over another at a given pH. As distribution coefficients capture both thermodynamic effects (the free energy of transfer between phases) and chemical effects (protonation state and tautomer effects in aqueous solution), they provide an exacting test of the thermodynamic and chemical accuracy of physical models without the long correlation times inherent to the prediction of more complex properties of relevance to drug discovery, such as protein-ligand binding affinities...
October 7, 2016: Journal of Computer-aided Molecular Design
Jiraphorn Phanich, Thanyada Rungrotmongkol, Nawee Kungwan, Supot Hannongbua
The H7N9 avian influenza virus is a novel re-assortment from at least four different strains of virus. Neuraminidase, which is a glycoprotein on the surface membrane, has been the target for drug treatment. However, some H7N9 strains that have been isolated from patient after drug treatment have a R292K mutation in neuraminidase. This substitution was found to facilitate drug resistance using protein- and virus- assays, in particular it gave a high resistance to the most commonly used drug, oseltamivir. The aim of this research is to understand the source of oseltamivir resistance using MD simulations and the MM/PB(GB)SA binding free energy approaches...
October 6, 2016: Journal of Computer-aided Molecular Design
Philip Prathipati, Chioko Nagao, Shandar Ahmad, Kenji Mizuguchi
The D3R 2015 grand drug design challenge provided a set of blinded challenges for evaluating the applicability of our protocols for pose and affinity prediction. In the present study, we report the application of two different strategies for the two D3R protein targets HSP90 and MAP4K4. HSP90 is a well-studied target system with numerous co-crystal structures and SAR data. Furthermore the D3R HSP90 test compounds showed high structural similarity to existing HSP90 inhibitors in BindingDB. Thus, we adopted an integrated docking and scoring approach involving a combination of both pharmacophoric and heavy atom similarity alignments, local minimization and quantitative structure activity relationships modeling, resulting in the reasonable prediction of pose [with the root mean square deviation (RMSD) values of 1...
October 6, 2016: Journal of Computer-aided Molecular Design
Sergio Ruiz-Carmona, Xavier Barril
Novel methods for drug discovery are constantly under development and independent exercises to test and validate them for different goals are extremely useful. The drug discovery data resource (D3R) Grand Challenge 2015 offers an excellent opportunity as an external assessment and validation experiment for Computer-Aided Drug Discovery methods. The challenge comprises two protein targets and prediction tests: binding mode and ligand ranking. We have faced both of them with the same strategy: pharmacophore-guided docking followed by dynamic undocking (a new method tested experimentally here) and, where possible, critical assessment of the results based on pre-existing information...
October 5, 2016: Journal of Computer-aided Molecular Design
Edithe Selwa, Virginie Y Martiny, Bogdan I Iorga
The D3R Grand Challenge 2015 was focused on two protein targets: Heat Shock Protein 90 (HSP90) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4). We used a protocol involving a preliminary analysis of the available data in PDB and PubChem BioAssay, and then a docking/scoring step using more computationally demanding parameters that were required to provide more reliable predictions. We could evidence that different docking software and scoring functions can behave differently on individual ligand datasets, and that the flexibility of specific binding site residues is a crucial element to provide good predictions...
October 3, 2016: Journal of Computer-aided Molecular Design
Nupur Bansal, Zheng Zheng, David S Cerutti, Kenneth M Merz
We review our performance in the SAMPL5 challenge for predicting host-guest binding affinities using the movable type (MT) method. The challenge included three hosts, acyclic Cucurbit[2]uril and two octa-acids with and without methylation at the entrance to their binding cavities. Each host was associated with 6-10 guest molecules. The MT method extrapolates local energy landscapes around particular molecular states and estimates the free energy by Monte Carlo integration over these landscapes. Two blind submissions pairing MT with variants of the KECSA potential function yielded mean unsigned errors of 1...
October 3, 2016: Journal of Computer-aided Molecular Design
Florentina Tofoleanu, Juyong Lee, Frank C Pickard Iv, Gerhard König, Jing Huang, Minkyung Baek, Chaok Seok, Bernard R Brooks
As part of the SAMPL5 blind prediction challenge, we calculate the absolute binding free energies of six guest molecules to an octa-acid (OAH) and to a methylated octa-acid (OAMe). We use the double decoupling method via thermodynamic integration (TI) or Hamiltonian replica exchange in connection with the Bennett acceptance ratio (HREM-BAR). We produce the binding poses either through manual docking or by using GalaxyDock-HG, a docking software developed specifically for this study. The root mean square deviations for our most accurate predictions are 1...
September 30, 2016: Journal of Computer-aided Molecular Design
Bipin Singh, Gopalakrishnan Bulusu, Abhijit Mitra
Molecular level understanding of mutational effects on stability and activity of enzymes is challenging particularly when several point mutations are incorporated during the directed evolution experiments. In our earlier study, we have suggested the lack of consistency in the effect of point mutations incorporated during the initial generations of directed evolution experiments, towards conformational stabilization of B. subtilis lipase mutants of later generations. Here, we report that the cumulative point mutations incorporated in mutants 2M (with two point mutations) to 6M (with six point mutations) possibly do not retain their original stabilizing nature in the most thermostable 12M mutant (with 12 point mutations)...
September 30, 2016: Journal of Computer-aided Molecular Design
Symon Gathiaka, Shuai Liu, Michael Chiu, Huanwang Yang, Jeanne A Stuckey, You Na Kang, Jim Delproposto, Ginger Kubish, James B Dunbar, Heather A Carlson, Stephen K Burley, W Patrick Walters, Rommie E Amaro, Victoria A Feher, Michael K Gilson
The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challenges for both target datasets were conducted in two stages, with the first stage testing pose predictions and the capacity to rank compounds by affinity with minimal structural data; and the second stage testing methods for ranking compounds with knowledge of at least a subset of the ligand-protein poses...
September 30, 2016: Journal of Computer-aided Molecular Design
Rajat Kumar Pal, Kamran Haider, Divya Kaur, William Flynn, Junchao Xia, Ronald M Levy, Tetiana Taran, Lauren Wickstrom, Tom Kurtzman, Emilio Gallicchio
As part of the SAMPL5 blinded experiment, we computed the absolute binding free energies of 22 host-guest complexes employing a novel approach based on the BEDAM single-decoupling alchemical free energy protocol with parallel replica exchange conformational sampling and the AGBNP2 implicit solvation model specifically customized to treat the effect of water displacement as modeled by the Hydration Site Analysis method with explicit solvation. Initial predictions were affected by the lack of treatment of ionic charge screening, which is very significant for these highly charged hosts, and resulted in poor relative ranking of negatively versus positively charged guests...
September 30, 2016: Journal of Computer-aided Molecular Design
Stefano Bosisio, Antonia S J S Mey, Julien Michel
In the context of the SAMPL5 challenge water-cyclohexane distribution coefficients for 53 drug-like molecules were predicted. Four different models based on molecular dynamics free energy calculations were tested. All models initially assumed only one chemical state present in aqueous or organic phases. Model A is based on results from an alchemical annihilation scheme; model B adds a long range correction for the Lennard Jones potentials to model A; model C adds charging free energy corrections; model D applies the charging correction from model C to ionizable species only...
September 27, 2016: Journal of Computer-aided Molecular Design
Caitlin C Bannan, Kalistyn H Burley, Michael Chiu, Michael R Shirts, Michael K Gilson, David L Mobley
In the recent SAMPL5 challenge, participants submitted predictions for cyclohexane/water distribution coefficients for a set of 53 small molecules. Distribution coefficients (log D) replace the hydration free energies that were a central part of the past five SAMPL challenges. A wide variety of computational methods were represented by the 76 submissions from 18 participating groups. Here, we analyze submissions by a variety of error metrics and provide details for a number of reference calculations we performed...
September 27, 2016: Journal of Computer-aided Molecular Design
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...
September 27, 2016: Journal of Computer-aided Molecular Design
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...
September 22, 2016: Journal of Computer-aided Molecular Design
Andrew Anighoro, Antonio de la Vega de León, Jürgen Bajorath
Macrocyclic compounds experience increasing interest in drug discovery. It is often thought that these large and chemically complex molecules provide promising candidates to address difficult targets and interfere with protein-protein interactions. From a computational viewpoint, these molecules are difficult to treat. For example, flexible docking of macrocyclic compounds is hindered by the limited ability of current docking approaches to optimize conformations of extended ring systems for pose prediction...
September 21, 2016: Journal of Computer-aided Molecular Design
Ingo Muegge, Andreas Bergner, Jan M Kriegl
Computer-Aided Drug Design (CADD) is an integral part of the drug discovery endeavor at Boehringer Ingelheim (BI). CADD contributes to the evaluation of new therapeutic concepts, identifies small molecule starting points for drug discovery, and develops strategies for optimizing hit and lead compounds. The CADD scientists at BI benefit from the global use and development of both software platforms and computational services. A number of computational techniques developed in-house have significantly changed the way early drug discovery is carried out at BI...
September 20, 2016: Journal of Computer-aided Molecular Design
Michael R Jones, Bernard R Brooks, Angela K Wilson
SAMPL challenges (Mobley et al. in J Comput Aided Mol Des 28:135-150, 2014; Skillman in J Comput Aided Mol Des 26:473-474, 2012; Geballe in J Comput Aided Mol Des 24:259-279, 2010; Guthrie in J Phys Chem B 113:4501-4507, 2009) provide excellent opportunities to assess theoretical approaches on new data sets with a goal of gaining greater insight towards protein and ligand modeling. In the SAMPL5 experiment, cyclohexane-water partition coefficients were determined using a vertical solvation scheme in conjunction with the SMD continuum solvent model...
September 19, 2016: Journal of Computer-aided Molecular Design
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