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Journal of Computer-aided Molecular Design

Andrea Rizzi, Steven Murkli, John N McNeill, Wei Yao, Matthew Sullivan, Michael K Gilson, Michael W Chiu, Lyle Isaacs, Bruce C Gibb, David L Mobley, John D Chodera
Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets...
November 10, 2018: Journal of Computer-aided Molecular Design
Mehtap Işık, Dorothy Levorse, Ariën S Rustenburg, Ikenna E Ndukwe, Heather Wang, Xiao Wang, Mikhail Reibarkh, Gary E Martin, Alexey A Makarov, David L Mobley, Timothy Rhodes, John D Chodera
Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transfer to another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with biological macromolecules using computational models...
November 7, 2018: Journal of Computer-aided Molecular Design
You-Lin Xue, Qiaoshi Zhang, Yuna Sun, Xiaohong Zhou, Ian P Hurley, Gary W Jones, Youtao Song
Genetics experiments have identified six mutations located in the subdomain IA (A17V, R23H, G32D, G32S, R34K, V372I) of Ssa1 that influence propagation of the yeast [PSI+ ] prion. However, the underlining molecular mechanisms of these mutations are still unclear. The six mutation sites are present in the IA subdomain of the nucleotide-binding domain (NBD). The ATPase subdomain IA is a critical mediator of inter-domain allostery in Hsp70 molecular chaperones, so the mutation and changes in this subdomain may influence the function of the substrate-binding domain...
November 3, 2018: Journal of Computer-aided Molecular Design
Laurence Leherte, Axel Petit, Denis Jacquemin, Daniel P Vercauteren, Adèle D Laurent
The CD2-CD58 protein-protein interaction is known to favor the recognition of antigen presenting cells by T cells. The structural, energetics, and dynamical properties of three known cyclic CD58 ligands, named P6, P7, and RTD-c, are studied through molecular dynamics (MD) simulations and molecular docking calculations. The ligands are built so as to mimic the C and F β-strands of protein CD2, connected via turn inducers. The MD analyses focus on the location of the ligands with respect to the experimental binding site and on the direct and water-mediated hydrogen bonds (H bonds) they form with CD58...
October 28, 2018: Journal of Computer-aided Molecular Design
E Srinivasan, R Rajasekaran
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that has been associated with mutations in metalloenzyme superoxide dismutase (SOD1) causing protein structural destabilization and aggregation. However, the mechanistic action and the cure for the disease still remain obscure. Herein, we initially studied the conformational preferences of SOD1 protein structures upon substitution of Ala at Gly93 in comparison with that of wild type. Our results corroborated with the previous experimental studies on the aggregation and the destabilizing activity of mutant SOD1 protein G93A...
October 28, 2018: Journal of Computer-aided Molecular Design
Gonzalo Cerruela García, Nicolás García-Pedrajas
Feature selection is commonly used as a preprocessing step to machine learning for improving learning performance, lowering computational complexity and facilitating model interpretation. This paper proposes the application of boosting feature selection to improve the classification performance of standard feature selection algorithms evaluated for the prediction of P-gp inhibitors and substrates. Two well-known classification algorithms, decision trees and support vector machines, were used to classify the chemical compounds...
October 26, 2018: Journal of Computer-aided Molecular Design
Julio Caballero, Alejandro Morales-Bayuelo, Carlos Navarro-Retamal
In the last decades, human protein kinases (PKs) have been relevant as targets in the development of novel therapies against many diseases, but the study of Mycobacterium tuberculosis PKs (MTPKs) involved in tuberculosis pathogenesis began much later and has not yet reached an advanced stage of development. To increase knowledge of these enzymes, in this work we studied the structural features of MTPKs, with focus on their ATP-binding sites and their interactions with inhibitors. PknA, PknB, and PknG are the most studied MTPKs, which were previously crystallized; ATP-competitive inhibitors have been designed against them in the last decade...
October 26, 2018: Journal of Computer-aided Molecular Design
Enrico Margiotta, Giuseppe Deganutti, Stefano Moro
The allosteric modulation of G protein-coupled receptors (GPCRs) by sodium ions has received considerable attention as crystal structures of several receptors, in their inactive conformation, show a Na+ ion bound to specific residues which, in the human A2A adenosine receptor (hA2A AR), are Ser913.39 , Trp2466.48 , Asn2807.45 , and Asn2847.49 . A cluster of water molecules completes the coordination of the sodium ion in the putative allosteric site. It is absolutely consolidated that the progress made in the field of GPCRs structural determination has increased the adoption of docking-driven approaches for the identification or the optimization of novel potent and selective ligands...
October 25, 2018: Journal of Computer-aided Molecular Design
Caitlin C Bannan, David L Mobley, A Geoffrey Skillman
A variety of fields would benefit from accurate [Formula: see text] predictions, especially drug design due to the effect a change in ionization state can have on a molecule's physiochemical properties. Participants in the recent SAMPL6 blind challenge were asked to submit predictions for microscopic and macroscopic [Formula: see text]s of 24 drug like small molecules. We recently built a general model for predicting [Formula: see text]s using a Gaussian process regression trained using physical and chemical features of each ionizable group...
October 15, 2018: Journal of Computer-aided Molecular Design
Naohiro Nishikawa, Kyungreem Han, Xiongwu Wu, Florentina Tofoleanu, Bernard R Brooks
We calculate the absolute binding free energies of tetra-methylated octa-acids host-guest systems as a part of the SAMPL6 blind challenge (receipt ID vq30p). We employed two different free energy simulation methods, i.e., the umbrella sampling (US) and double decoupling method (DDM). The US method was used with the weighted histogram analysis method (WHAM) (US-WHAM scheme). In the DDM scheme, Hamiltonian replica-exchange method (HREM) was combined with the Bennett acceptance ratio (BAR) (HREM-BAR scheme). We obtained initial binding poses via molecular docking using GalaxyDock-HG program, which is developed for the SAMPL challenge...
October 15, 2018: Journal of Computer-aided Molecular Design
Marie L Laury, Zhi Wang, Aaron S Gordon, Jay W Ponder
As part of the SAMPL6 host-guest blind challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for a cucurbit[8]uril host complexed with 14 diverse guests, ranging from small, rigid structures to drug molecules. The AMOEBA results from the initial submission prompted an investigation into aspects of the methodology and parameterization employed. Lessons learned from the blind challenge include: a double annihilation scheme (electrostatics and van der Waals) is needed to obtain proper sampling of guest conformations, annihilation of key torsion parameters of the guest are recommended for flexible guests, and a more thorough analysis of torsion parameters is warranted...
October 15, 2018: Journal of Computer-aided Molecular Design
Samarjeet Prasad, Jing Huang, Qiao Zeng, Bernard R Brooks
In this work we have developed a hybrid QM and MM approach to predict pKa of small drug-like molecules in explicit solvent. The gas phase free energy of deprotonation is calculated using the M06-2X density functional theory level with Pople basis sets. The solvation free energy difference of the acid and its conjugate base is calculated at MD level using thermodynamic integration. We applied this method to the 24 drug-like molecules in the SAMPL6 blind pKa prediction challenge. We achieved an overall RMSE of 2...
October 1, 2018: Journal of Computer-aided Molecular Design
Phillip S Hudson, Kyungreem Han, H Lee Woodcock, Bernard R Brooks
Use of quantum mechanical/molecular mechanical (QM/MM) methods in binding free energy calculations, particularly in the SAMPL challenge, often fail to achieve improvement over standard additive (MM) force fields. Frequently, the implementation is through use of reference potentials, or the so-called "indirect approach", and inherently relies on sufficient overlap existing between MM and QM/MM configurational spaces. This overlap is generally poor, particularly for the use of free energy perturbation to perform the MM to QM/MM free energy correction at the end states of interest (e...
October 1, 2018: Journal of Computer-aided Molecular Design
P Siani, H Khandelia, M Orsi, L G Dias
We present a new coarse-grained (CG) model of cholesterol (CHOL) for the electrostatic-based ELBA force field. A distinguishing feature of our CHOL model is that the electrostatics is modeled by an explicit point dipole which interacts through an ideal vacuum permittivity. The CHOL model parameters were optimized in a systematic fashion, reproducing the electrostatic and nonpolar partitioning free energies of CHOL in lipid/water mixtures predicted by full-detailed atomistic molecular dynamics simulations. The CHOL model has been validated by comparison to structural, dynamic and thermodynamic properties with experimental and atomistic simulation reference data...
September 26, 2018: Journal of Computer-aided Molecular Design
Yiğitcan Eken, Prajay Patel, Thomas Díaz, Michael R Jones, Angela K Wilson
In this effort in the SAMPL6 host-guest binding challenge, a combination of molecular dynamics and quantum mechanical methods were used to blindly predict the host-guest binding free energies of a series of cucurbit[8]uril (CB8), octa-acid (OA), and tetramethyl octa-acid (TEMOA) hosts bound to various guest molecules in aqueous solution. Poses for host-guest systems were generated via molecular dynamics (MD) simulations and clustering analyses. The binding free energies for the structures obtained via cluster analyses of MD trajectories were calculated using the MMPBSA method and density functional theory (DFT) with the inclusion of Grimme's dispersion correction, an implicit solvation model to model the aqueous solution, and the resolution-of-the-identity (RI) approximation (MMPBSA, RI-B3PW91-D3, and RI-B3PW91, respectively)...
September 17, 2018: Journal of Computer-aided Molecular Design
Xibing He, Viet H Man, Beihong Ji, Xiang-Qun Xie, Junmei Wang
We participated in the Cathepsin S (CatS) sub-challenge of the Drug Design Data Resource (D3R) Grand Challenge 3 (GC3) in 2017 to blindly predict the binding poses of 24 CatS-bound ligands, the binding affinity ranking of 136 ligands, and the binding free energies of a subset of 33 ligands in Stage 1A and Stage 2. Our submitted predictions ranked relatively well compared to the submissions from other participants. Here we present our methodologies used in the challenge. For the binding pose prediction, we employed the Glide module in the Schrodinger Suite 2017 and AutoDock Vina...
September 14, 2018: Journal of Computer-aided Molecular Design
Irena Majerz
Dimers of furan, 2,3-dihydrofuran, 2,5-dihydrofuran and tetrahydrofuran were investigated with the use of theoretical methods to determine the interactions that keep the molecules together. The QTAIM and NCI methods confirmed that for furan dimers the C-H⋯O hydrogen bond and stacking interactions can form the dimers with similar energy. For 2,3-dihydrofuran, 2,5-dihydrofuran and tetrahydrofuran, the decisive mechanism of dimer formation is the stacking interaction between the furan rings.
September 14, 2018: Journal of Computer-aided Molecular Design
Ludovic Chaput, Edithe Selwa, Eddy Elisée, Bogdan I Iorga
During the last few years, we have developed a docking protocol involving two steps: (i) the choice of the most appropriate docking software and parameters for the system of interest using structural and functional information available in public databases (PDB, ChEMBL, PubChem Assay, BindingDB, etc.); (ii) the docking of ligand dataset to provide a prediction for the binding modes and ranking of ligands. We applied this protocol to the D3R Grand Challenge 3 dataset containing cathepsin S (CatS) inhibitors...
September 11, 2018: Journal of Computer-aided Molecular Design
Octav Caldararu, Martin A Olsson, Majda Misini Ignjatović, Meiting Wang, Ulf Ryde
We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP...
September 10, 2018: Journal of Computer-aided Molecular Design
Noriyuki Yamaotsu, Shuichi Hirono
Here, we propose an in silico fragment-mapping method as a potential tool for fragment-based/structure-based drug discovery (FBDD/SBDD). For this method, we created a database named Canonical Subsite-Fragment DataBase (CSFDB) and developed a knowledge-based fragment-mapping program, Fsubsite. CSFDB consists of various pairs of subsite-fragments derived from X-ray crystal structures of known protein-ligand complexes. Using three-dimensional similarity-matching between subsites on one protein and another, Fsubsite compares the surface of a target protein with all subsites in CSFDB...
September 8, 2018: Journal of Computer-aided Molecular Design
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