Structural Fluctuations of Aromatic Residues in an Apo-Form Reveal Cryptic Binding Sites: Implications for Fragment-Based Drug Design.

Cryptic sites are binding pockets that are transiently formed in an apo form or that are induced by ligand binding. The investigation of cryptic sites is crucial for drug discovery, since these sites are ubiquitous in disease-related human proteins, and targeting them expands the number of drug targets greatly. However, although many computational studies have attempted to identify cryptic sites, the detection remains challenging.

A adenosine receptor inhibition by the dihydropyridine calcium channel blocker nifedipine involves colonic fluid secretion.

The adenosine A receptor is a critical protein in intestinal water secretion. In the present study, we screened compound libraries to identify inhibitors of the A receptor and evaluated their effect on adenosine-induced intestinal fluid secretion. The screening identified the dihydropyridine calcium antagonists nifedipine and nisoldipine.

Prediction of Passive Membrane Permeability by Semi-Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion.

Membrane permeability is an important property of drugs in adsorption. Many prediction methods work well for small molecules, but the prediction of middle-molecule permeability is still difficult. In the present study, we modified a classical permeability model based on Fick's law to study passive membrane permeability.

Prediction of Protein-compound Binding Energies from Known Activity Data: Docking-score-based Method and its Applications.

We used protein-compound docking simulations to develop a structure-based quantitative structure-activity relationship (QSAR) model. The prediction model used docking scores as descriptors. The binding free energy was approximated by a weighted average of docking scores for multiple proteins.

myPresto/omegagene: a GPU-accelerated molecular dynamics simulator tailored for enhanced conformational sampling methods with a non-Ewald electrostatic scheme.

Molecular dynamics (MD) is a promising computational approach to investigate dynamical behavior of molecular systems at the atomic level. Here, we present a new MD simulation engine named "myPresto/omegagene" that is tailored for enhanced conformational sampling methods with a non-Ewald electrostatic potential scheme. Our enhanced conformational sampling methods, , the virtual-system-coupled multi-canonical MD (V-McMD) method, replace a multi-process parallelized run with multiple independent runs to avoid inter-node communication overhead.

Variation of free-energy landscape of the p53 C-terminal domain induced by acetylation: Enhanced conformational sampling.

The C-terminal domain (CTD) of tumor suppressor protein p53 is an intrinsically disordered region that binds to various partner proteins, where lysine of CTD is acetylated/nonacetylated and histidine neutralized/non-neutralized. Because of the flexibility of the unbound CTD, a free-energy landscape (FEL) is a useful quantity for determining its statistical properties. We conducted enhanced conformational sampling of CTD in the unbound state via virtual system coupled multicanonical molecular dynamics, in which the lysine was acetylated or nonacetylated and histidine was charged or neutralized.

Elastic properties of dynein motor domain obtained from all-atom molecular dynamics simulations.

Dyneins are large microtubule motor proteins that convert ATP energy to mechanical power. High-resolution crystal structures of ADP-bound cytoplasmic dynein have revealed the organization of the motor domain, comprising the AAA(+) ring, the linker, the stalk/strut and the C sequence. Recently, the ADP.

Miscellaneous Topics in Computer-Aided Drug Design: Synthetic Accessibility and GPU Computing, and Other Topics.

Computer-aided drug design is still a state-of-the-art process in medicinal chemistry, and the main topics in this field have been extensively studied and well reviewed. These topics include compound databases, ligand-binding pocket prediction, protein-compound docking, virtual screening, target/off-target prediction, physical property prediction, molecular simulation and pharmacokinetics/pharmacodynamics (PK/PD) prediction. Message and Conclusion: However, there are also a number of secondary or miscellaneous topics that have been less well covered.

Virtual-system-coupled adaptive umbrella sampling to compute free-energy landscape for flexible molecular docking.

A novel enhanced conformational sampling method, virtual-system-coupled adaptive umbrella sampling (V-AUS), was proposed to compute 300-K free-energy landscape for flexible molecular docking, where a virtual degrees of freedom was introduced to control the sampling. This degree of freedom interacts with the biomolecular system. V-AUS was applied to complex formation of two disordered amyloid-β (Aβ30-35 ) peptides in a periodic box filled by an explicit solvent.

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities.

Chronic obstructive pulmonary disease (COPD) is characterized by abnormal inflammatory responses and airflow limitations. We recently proposed that the muscarinic antagonist mepenzolate bromide (mepenzolate) would be therapeutically effective against COPD due to its muscarinic receptor-dependent bronchodilatory activity as well as anti-inflammatory properties. Mepenzolate has an asymmetric carbon atom, thus providing us with the opportunity to synthesize both of its enantiomers ((R)- and (S)-mepenzolate) and to examine their biochemical and pharmacological activities.

Molecular Dynamics Simulations Accelerated by GPU for Biological Macromolecules with a Non-Ewald Scheme for Electrostatic Interactions.

A molecular dynamics (MD) simulation program for biological macromolecules was implemented with a non-Ewald scheme for long-ranged electrostatic interactions and run on a general purpose graphics processing unit (GPU). We recently developed several non-Ewald methods to compute the electrostatic energies with high precision. In particular, the zero-dipole summation (ZD) method, which takes into account the neutralities of charges and dipoles in a truncated subset, enables the calculation of electrostatic interactions with high accuracy and low computational cost, and its algorithm is simple enough to be implemented in a GPU.

In silico fragment screening by replica generation (FSRG) method for fragment-based drug design.

We developed a new in silico screening method, which is a structure-based virtual fragment screening with protein-compound docking. The structure-based in silico screening of small fragments is known to be difficult due to poor surface complementarity between protein surfaces and small compound (fragment) surfaces. In our method, several side chains were attached to the fragment in question to generate a set of replica molecules of different sizes.