Assessing the performance of MM/PBSA and MM/GBSA methods. 8. Predicting binding free energies and poses of protein-RNA complexes.

Molecular docking provides a computationally efficient way to predict the atomic structural details of protein-RNA interactions (PRI), but accurate prediction of the three-dimensional structures and binding affinities for PRI is still notoriously difficult, partly due to the unreliability of the existing scoring functions for PRI. MM/PBSA and MM/GBSA are more theoretically rigorous than most scoring functions for protein-RNA docking, but their prediction performance for protein-RNA systems remains unclear. Here, we systemically evaluated the capability of MM/PBSA and MM/GBSA to predict the binding affinities and recognize the near-native binding structures for protein-RNA systems with different solvent models and interior dielectric constants ().

Cheminformatic Insight into the Differences between Terrestrial and Marine Originated Natural Products.

This is a new golden age for drug discovery based on natural products derived from both marine and terrestrial sources. Herein, a straightforward but important question is "what are the major structural differences between marine natural products (MNPs) and terrestrial natural products (TNPs)?" To answer this question, we analyzed the important physicochemical properties, structural features, and drug-likeness of the two types of natural products and discussed their differences from the perspective of evolution. In general, MNPs have lower solubility and are often larger than TNPs.

Assessing the performance of MM/PBSA and MM/GBSA methods. 7. Entropy effects on the performance of end-point binding free energy calculation approaches.

Entropy effects play an important role in drug-target interactions, but the entropic contribution to ligand-binding affinity is often neglected by end-point binding free energy calculation methods, such as MM/GBSA and MM/PBSA, due to the expensive computational cost of normal mode analysis (NMA). Here, we systematically investigated entropy effects on the prediction power of MM/GBSA and MM/PBSA using >1500 protein-ligand systems and six representative AMBER force fields. Two computationally efficient methods, including NMA based on truncated structures and the interaction entropy approach, were used to estimate the entropic contributions to ligand-target binding free energies.

Fullerene derivatives act as inhibitors of leukocyte common antigen based on molecular dynamics simulations.

Fullerene-based molecules are being studied as potential inhibitors of protein tyrosine phosphatases due to their unique properties and low toxicity. However, the underlying molecular mechanism remains elusive. In this study, molecular dynamics (MD) simulations in conjunction with molecular docking calculations were utilized to investigate the binding effects of C, C(NH), and C(OH) on the enzymatic activity of CD45 (a receptor-like protein tyrosine phosphatase).

Macrophage migration inhibitory factor (MIF) inhibitor, Z-590 suppresses cartilage destruction in adjuvant-induced arthritis via inhibition of macrophage inflammatory activation.

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator that is involved in the progression of rheumatoid arthritis (RA). Previously, we demonstrated a small molecule compound 3-[(biphenyl-4-ylcarbonyl) carbamothioyl] amino benzoic acid (Z-590) could inhibit MIF activity with docking-based virtual screening and experimental evaluation.

Methods: The LPS activated RAW264.

Benchmark Study Based on 2P2I to Gain Insights into the Discovery of Small-Molecule PPI Inhibitors.

Protein-protein interactions (PPIs) have been regarded as novel and highly promising drug targets in drug discovery. Numerous new experimental techniques and computational approaches have been developed to assist the design of PPI modulators during the past two decades. However, identification and optimization of small-molecule inhibitors targeting PPIs is still a particularly challenging task due to the "undruggable" profiles of PPI interfaces.

Importance of protein flexibility in molecular recognition: a case study on Type-I1/2 inhibitors of ALK.

Anaplastic lymphoma kinase (ALK) has been regarded as a promising target for the therapy of various cancers. A large number of ALK inhibitors with diverse scaffolds have been discovered, and most of them belong to Type-I inhibitors that only occupy the ATP-binding pocket. Recently, we reported a series of novel and potent Type-I1/2 inhibitors of ALK with the 1-purine-3-piperidinecarboxamide scaffold, which can bind to both the ATP-binding site of ALK and the adjacent hydrophobic allosteric pocket.

HawkRank: a new scoring function for protein-protein docking based on weighted energy terms.

Deciphering the structural determinants of protein-protein interactions (PPIs) is essential to gain a deep understanding of many important biological functions in the living cells. Computational approaches for the structural modeling of PPIs, such as protein-protein docking, are quite needed to complement existing experimental techniques. The reliability of a protein-protein docking method is dependent on the ability of the scoring function to accurately distinguish the near-native binding structures from a huge number of decoys.

Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation.

Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of "bridge" inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK.

Comparative analyses of structural features and scaffold diversity for purchasable compound libraries.

Large purchasable screening libraries of small molecules afforded by commercial vendors are indispensable sources for virtual screening (VS). Selecting an optimal screening library for a specific VS campaign is quite important to improve the success rates and avoid wasting resources in later experimental phases. Analysis of the structural features and molecular diversity for different screening libraries can provide valuable information to the decision making process when selecting screening libraries for VS.

ADMET Evaluation in Drug Discovery. 18. Reliable Prediction of Chemical-Induced Urinary Tract Toxicity by Boosting Machine Learning Approaches.

Xenobiotic chemicals and their metabolites are mainly excreted out of our bodies by the urinary tract through the urine. Chemical-induced urinary tract toxicity is one of the main reasons that cause failure during drug development, and it is a common adverse event for medications, natural supplements, and environmental chemicals. Despite its importance, there are only a few in silico models for assessing urinary tract toxicity for a large number of compounds with diverse chemical structures.

Aggregated Single-Walled Carbon Nanotubes Absorb and Deform Dopamine-Related Proteins Based on Molecular Dynamics Simulations.

Single-walled carbon nanotubes (SWCNTs) have attracted considerable attention owing to their applications in various fields such as biotechnology and biomedicine. Recently, aggregated SWCNTs have shown more significant effects on the treatment of methamphetamine addiction (Nat. Nanotech.

Discovery of a ROCK inhibitor, FPND, which prevents cerebral hemorrhage through maintaining vascular integrity by interference with VE-cadherin.

Hemorrhagic stroke occurs when a weakened vessel ruptures and bleeds into the surrounding brain, leading to high rates of death and disability worldwide. A series of complex pathophysiological cascades contribute to the risk of hemorrhagic stroke, and no therapies have proven effective to prevent hemorrhagic stroke. Stabilization of vascular integrity has been considered as a potential therapeutic target for hemorrhagic stroke.

How Does the L884P Mutation Confer Resistance to Type-II Inhibitors of JAK2 Kinase: A Comprehensive Molecular Modeling Study.

Janus kinase 2 (JAK2) has been regarded as an essential target for the treatment of myeloproliferative neoplasms (MPNs). BBT594 and CHZ868, Type-II inhibitors of JAK2, illustrate satisfactory efficacy in preclinical MPNs and acute lymphoblastic leukemia (ALL) models. However, the L884P mutation of JAK2 abrogates the suppressive effects of BBT594 and CHZ868.

Characterizing Drug-Target Residence Time with Metadynamics: How To Achieve Dissociation Rate Efficiently without Losing Accuracy against Time-Consuming Approaches.

Drug-target residence time plays a vital role in drug efficacy. However, there is still no effective strategy to predict drug residence time. Here, we propose to use the optimized (or minimized) structures derived from holo-state proteins to calculate drug residence time, which could give a comparable or even better prediction accuracy compared with those calculated utilizing a large number of molecular dynamics (MD) structures based on the Poisson process.

Monolayer germanium monochalcogenides (GeS/GeSe) as cathode catalysts in nonaqueous Li-O batteries.

The development of novel cathode catalysts is of great importance to the practical applications of nonaqueous lithium oxygen (Li-O) batteries. Here by using first-principles calculations, we revealed the catalytic mechanism and evaluated the catalytic activity of monolayer germanium monochalcogenides (2D-GeXs, X = S/Se) as cathode catalytic materials. For 2D-GeXs, LiO with a ring-like structure is the final discharge product.

ADMET Evaluation in Drug Discovery. Part 17: Development of Quantitative and Qualitative Prediction Models for Chemical-Induced Respiratory Toxicity.

As a dangerous end point, respiratory toxicity can cause serious adverse health effects and even death. Meanwhile, it is a common and traditional issue in occupational and environmental protection. Pharmaceutical and chemical industries have a strong urge to develop precise and convenient computational tools to evaluate the respiratory toxicity of compounds as early as possible.

Discovery of Novel and Selective Adenosine A Receptor Antagonists for Treating Parkinson's Disease through Comparative Structure-Based Virtual Screening.

Among non-dopaminergic strategies for combating Parkinson's disease (PD), antagonism of the A adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against the A AR (K < 10 μM), including two compounds with K below 1 μM (compound 43, 0.

Two-dimensional germanium monochalcogenide photocatalyst for water splitting under ultraviolet, visible to near-infrared light.

Full utilization of solar energy to split water into hydrogen and oxygen is an efficient way to solve the current energy problem. Graphene-like germanium monochalcogenides (GeS or GeSe) are proposed here as efficient photocatalysts for water splitting under a broad range from ultraviolet, visible to near-infrared light dependent on their thickness. Compared to traditional photocatalysts, GeS and GeSe possess a large intrinsic dipole and introduce an internal electric field directing from Ge surface to S/Se surface, which causes notable band bending.

Exploring the RNA-bound and RNA-free human Argonaute-2 by molecular dynamics simulation method.

Argonaute 2 (Ago2) protein is the major vehicle of microRNAs (miRNAs)-guided gene repression and silencing processes. Although the crystal structure of human Ago2 (hAgo2) has recently been disclosed, the information of dynamically structural character of protein-RNA recognition is still lacking. Molecular dynamics simulations were used to systematically explore hAgo2 in the presence and absence of RNA duplex.

Prediction of luciferase inhibitors by the high-performance MIEC-GBDT approach based on interaction energetic patterns.

High-throughput screening (HTS) is widely applied in many fields ranging from drug discovery to clinical diagnostics and toxicity assessment. Firefly luciferase is commonly used as a reporter to monitor the effect of chemical compounds on the activity of a specific target or pathway in HTS. However, the false positive rate of luciferase-based HTS is relatively high because many artifacts or promiscuous compounds that have direct interaction with the luciferase reporter enzyme are usually identified as active compounds (hits).

Improving the Efficiency of Non-equilibrium Sampling in the Aqueous Environment via Implicit-Solvent Simulations.

By means of estimators based on non-equilibrium work, equilibrium free energy differences or potentials of mean force (PMFs) of a system of interest can be computed from biased molecular dynamics (MD) simulations. The approach, however, is often plagued by slow conformational sampling and poor convergence, especially when the solvent effects are taken into account. Here, as a possible way to alleviate the problem, several widely used implicit-solvent models, which are derived from the analytic generalized Born (GB) equation and implemented in the AMBER suite of programs, were employed in free energy calculations based on non-equilibrium work and evaluated for their abilities to emulate explicit water.

Atomistic Origins of Surface Defects in CHNHPbBr Perovskite and Their Electronic Structures.

The inherent instability of CHNHPbX remains a major technical barrier for the industrial applications of perovskite materials. Recently, the most stable surface structures of CHNHPbX have been successfully characterized by using density functional theory (DFT) calculations together with the high-resolution scanning tunneling microscopy (STM) results. The two coexisting phases of the perovskite surfaces have been ascribed to the alternate orientation of the methylammonium (MA) cations.

Peptide-Tethered Hydrogel Scaffold Promotes Recovery from Spinal Cord Transection via Synergism with Mesenchymal Stem Cells.

Spinal cord injury (SCI) is one of the most devastating injuries. Treatment strategies for SCI are required to overcome comprehensive issues. Implantation of biomaterial scaffolds and stem cells has been demonstrated to be a promising strategy.