Article
Chemistry, Physical
Zhiyi Wu, Philip C. Biggin
Summary: Absolute binding free-energy calculations play a crucial role in drug design, but accuracy is of utmost importance. This study explores the most suitable approach for simulation boxes containing lipid bilayers, and introduces the Rocklin correction method for lipid bilayer systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Biology
Juan L. Benavente, Dritan Siliqi, Lourdes Infantes, Laura Lagartera, Alberto Mills, Federico Gago, Noemi Ruiz-Lopez, Miguel A. Botella, Maria J. Sanchez-Barrena, Armando Albert
Summary: Extended synaptotagmins play a central role in non-vesicular lipid transfer between the ER and plasma membrane, acting as molecular tethers and lipid transfer proteins. They integrate different molecular signals in response to stress by binding to lipids through a Ca2+-dependent site and a site for phosphorylated forms of phosphatidylinositol, while their highly flexible hinge points facilitate lipid extraction, protein loading, and transfer between the plasma membrane and ER.
LIFE SCIENCE ALLIANCE
(2021)
Article
Chemistry, Multidisciplinary
Lea El Khoury, Zhifeng Jing, Alberto Cuzzolin, Alessandro Deplano, Daniele Loco, Boris Sattarov, Florent Hedin, Sebastian Wendeborn, Chris Ho, Dina El Ahdab, Theo Jaffrelot Inizan, Mattia Sturlese, Alice Sosic, Martina Volpiana, Angela Lugato, Marco Barone, Barbara Gatto, Maria Ludovica Macchia, Massimo Bellanda, Roberto Battistutta, Cristiano Salata, Ivan Kondratov, Rustam Iminov, Andrii Khairulin, Yaroslav Mykhalonok, Anton Pochepko, Volodymyr Chashka-Ratushnyi, Iaroslava Kos, Stefano Moro, Matthieu Montes, Pengyu Ren, Jay W. Ponder, Louis Lagardere, Jean-Philip Piquemal, Davide Sabbadin
Summary: We report a computationally driven discovery of new SARS-CoV-2 main protease (M-pro) inhibitors, whose potency has been significantly improved from initial non-covalent ligands to final covalent compound. The study highlights the power of structure-based computational strategies for drug design and provides insights for further optimization of M-pro inhibitors.
Article
Chemistry, Physical
Oliver J. Melling, Marley L. Samways, Yunhui Ge, David L. Mobley, Jonathan W. Essex
Summary: Water molecules are crucial in biomolecular systems, especially at protein-ligand interfaces. However, simulating such systems is challenging due to slow water exchange between protein and solvent. To overcome this, the authors combine grand canonical Monte Carlo (GCMC) with nonequilibrium candidate Monte Carlo (NCMC) to develop grand canonical nonequilibrium candidate Monte Carlo (GCNCMC). This approach improves water sampling efficiency and enables the exploration of new ligand-binding geometries mediated by water.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Carlos A. Ramos-Guzman, Milorad Andjelkovic, Kirill Zinovjev, J. Javier Ruiz-Pernia, Inaki Tunon
Summary: In this study, the by-residue decomposition of noncovalent interactions and analysis of naturally occurring mutations were used to detect potential mutations in the 3CL protease of SARS-CoV-2 that confer resistance to nirmatrelvir. It was found that the E166V mutation reduces the binding affinity of the protease to nirmatrelvir and increases the activation free energy for the formation of the covalent enzyme-inhibitor complex, resulting in resistance to the treatment with this drug. The conclusions of this study can be useful for predicting the consequences of introducing nirmatrelvir in the virus fitness landscape and designing new inhibitors targeting possible resistance mechanisms.
Article
Biochemistry & Molecular Biology
Saravanan Konda Mani, Ramesh Thiyagarajan, Olli Yli-Harja, Meenakshisundaram Kandhavelu, Akshaya Murugesan
Summary: The human GPR17 receptor acts as a biomarker for neurological diseases. Two isoforms, long and short, of GPR17 are found in human brain tissue. The structure of the long isoform has been studied, but the structure and activation mechanism of the short isoform remain unclear. In this study, the researchers modeled the structure of the short isoform and identified two distinct ligand binding sites. The binding of the endogenous ligand UDP was found to be stronger in both binding sites, suggesting its importance in the signaling and communication properties of GPR17. These findings may contribute to the development of targeted therapies for neurological diseases.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Article
Energy & Fuels
Priyanka Tavhare, Elby Titus, Ajay Chaudhari
Summary: The hydrogen storage properties of metal doped benzene complexes were found to vary depending on the positions of boron atom substitution. Ti-doped boron substituted complexes showed higher H2 uptake capacity and stronger interaction with adsorbed hydrogen molecules compared to Li, Be, and Ca-doped complexes, making them promising materials for hydrogen storage.
INTERNATIONAL JOURNAL OF ENERGY RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Erich Michel, Stefano Cucuzza, Peer R. E. Mittl, Oliver Zerbe, Andreas Plueckthun
Summary: The study aims to improve the stability of proteins for applications in therapeutics, diagnostics, and basic research. By designing a novel N-cap protein, the stability of proteins was successfully enhanced, addressing the issue of partial unfolding and making the proteins more resistant to proteolysis and aggregation.
Article
Biophysics
Eugene Klyshko, Justin Sung-Ho Kim, Sarah Rauscher
Summary: Accurate modeling of protein-water interactions is crucial for understanding protein function. We propose a method called LAWS based on multilateration to track crystallographic water sites (CWS) in molecular dynamics simulations. Compared with existing methods, LAWS defines CWS with more prominent water density peaks and a less-perturbed protein environment.
BIOPHYSICAL JOURNAL
(2023)
Article
Chemistry, Multidisciplinary
Rui Guo, Eirini Goudeli, Wanjun Xu, Joseph J. Richardson, Weijian Xu, Shuaijun Pan
Summary: The ability to effectively bind fluorinated motifs to various substrates using cyanoacrylate glue is computationally and experimentally evaluated. The composite coatings show ultralow surface energy and strong surface adhesion, allowing for the generation of super-repellent coatings. These coatings exhibit super-repellency to corrosive liquids and ultralow surface tension liquids, with tunable resistance to liquid penetration. They also demonstrate effective cargo loading and robust self-cleaning properties.
Article
Chemistry, Multidisciplinary
Istvan Horvath, David J. Wales, Szilard N. Fejer
Summary: Palladium ions complexed with nonlinear bidentate ligands can form hollow spherical shells. By using model anisotropic mesoscale building blocks, we can reproduce these structures and identify highly cooperative transitions between different polyhedral structures. The curvature of the ligand particles determines the preferred curvature of the building blocks.
NANOSCALE ADVANCES
(2022)
Review
Chemistry, Multidisciplinary
Jacopo Manigrasso, Marco Marcia, Marco De Vivo
Summary: The text discusses the identification of certain RNAs as druggable targets for small molecules in recent years and the challenges in targeting regulatory RNAs due to their structural flexibility and poorly understood structure-function relationships. It also highlights the adjustments made in standard drug-discovery approaches to optimize RNA-targeted small molecules, and examines the use of molecular modeling, docking, simulations, and computational tools in structure-based drug design for RNA targets.
Article
Multidisciplinary Sciences
He Tian, Kathryn M. Gunnison, Manija A. Kazmi, Thomas P. Sakmar, Thomas Huber
Summary: In this study, Rho mutants were engineered as FRET sensors to measure the kinetics and energetics of 11CR binding using genetic code expansion and bioorthogonal labeling. The study found that mutations in the channel between transmembrane helices 5 and 6 dramatically affected 11CR binding kinetics, but not agonist release kinetics. The findings provided direct experimental evidence for the entry of 11CR between TM5/6 in Rho, involving dynamic allosteric control of the ligand entry channel. These findings proposed a conceptual framework for understanding the function of G protein-coupled receptors with hydrophobic ligands that enter their binding pockets through transmembrane pores.
Article
Biochemistry & Molecular Biology
Pedro Renault, Jesus Giraldo
Summary: Computational tools have been used to estimate the druggability of allosteric sites in GPCRs, but predicting hydrophobic sites remains challenging. This study introduces a dynamics-based approach using experimental structures, normal mode analysis, and molecular dynamics simulations to identify allosteric sites in beta 2AR, GCGR, and M2 receptors, showing promising predictive value.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Dipendra Bhandari, Sangita Kachhap, Geet Madhukar, Kiran Kumar Adepu, Andriy Anishkin, Jin-Ran Chen, Sree V. Chintapalli
Summary: Previous research has shown that metabolites of phenolic acids (PAs) produced by gut microflora can promote bone development and protect against bone degeneration. This study uses computational strategies to understand the molecular interactions between hippuric acid (HA) and G-protein-coupled receptor 109A (GPR109A) and GPR109B. The results suggest that HA binds to GPR109A in a similar way to niacin and has a higher affinity for GPR109A than GPR109B.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Endocrinology & Metabolism
Nur Shabrina Amirruddin, Wei Xuan Tan, Yaw Sing Tan, Daphne Su-Lyn Gardner, Yong Mong Bee, Chandra Shekhar Verma, Shawn Hoon, Kok Onn Lee, Adrian Kee Keong Teo
Summary: This study examined the effects of heterozygous human INS gene mutations on insulin secretion and ER stress, revealing that mutant INS induces ER stress and defects in insulin processing, leading to decreased insulin secretion. Overexpression of mutant INS resulted in dominant-negative effects on insulin secretory capacity of beta cells after 9 weeks, with compensatory upregulation of genes involved in insulin secretion observed in patient-derived beta-like cells.
Article
Multidisciplinary Sciences
Blaise Su Jun Low, Chang Siang Lim, Shirley Suet Lee Ding, Yaw Sing Tan, Natasha Hui Jin Ng, Vidhya Gomathi Krishnan, Su Fen Ang, Claire Wen Ying Neo, Chandra S. Verma, Shawn Hoon, Su Chi Lim, E. Shyong Tai, Adrian Kee Keong Teo
Summary: HNF1A mutations can lead to MODY3, causing insulin secretion defects. Study using patient hiPSC-derived cells shows that HNF1A mutation decreases GLUT2 expression, impacting glucose uptake and ATP production.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Bibek Bhatta, Ishai Luz, Christian Krueger, Fanny Xueting Teo, David P. Lane, Kanaga Sabapathy, Tomer Cooks
Summary: Extracellular vesicles (EVs) released by cancer cells play a crucial role in transferring molecular information and reprogramming the tumor microenvironment. Mutations in the TP53 gene, encoding the p53 protein, lead to loss of tumor-suppressive properties and acquisition of novel functions that promote cancer growth. This study demonstrates that mutant p53 proteins can be transferred via EVs to neighboring cancer cells and immune cells, modulating them to support tumor growth.
Article
Chemistry, Physical
Justin Tze-Yang Ng, Yaw Sing Tan
Summary: This study reports the development of a new method, accelerated ligand-mapping MD (aLMMD), for detecting challenging binding sites. The method is able to detect and sample cryptic pockets and occluded binding sites, and may serve as a general approach for structure-based drug design in proteins.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Multidisciplinary Sciences
Samira Sadeghi, Siddharth Deshpande, Girish Vallerinteavide Mavelli, Alphan Aksoyoglu, Jayesh Bafna, Mathias Winterhalter, R. Manjunatha Kini, David P. Lane, Chester L. Drum
Summary: In vitro protein folding often leads to aggregation and low yields. Researchers have used nanoscale exoshells to enhance soluble yield, functional yield, and specific activity of folded proteins.
NATURE COMMUNICATIONS
(2021)
Article
Cell Biology
Vishnu Suresh Babu, Ashwin Mallipatna, Deepak Sa, Gagan Dudeja, Ramaraj Kannan, Rohit Shetty, Archana Padmanabhan Nair, Seetharamanjaneyulu Gundimeda, Shyam S. Chaurasia, Navin Kumar Verma, Rajamani Lakshminarayanan, Stephane Heymans, Veluchamy A. Barathi, Nilanjan Guha, Arkasubhra Ghosh
Summary: This study reveals unique functional associations between genes and metabolites in retinoblastoma (Rb) tumors. The gene expression patterns and metabolic processes differ between clinically advanced and non-advanced Rb, indicating altered tumor-specific metabolism. Rb tumors have reduced reliance on glycolytic pathways and are regulated by Rb1 and HK1.
Article
Chemistry, Multidisciplinary
Sophia S. Y. Chan, Denise Lee, Maria Prisca Meivita, Lunna Li, Yaw Sing Tan, Natasa Bajalovic, Desmond K. Loke
Summary: This study demonstrates the use of carbon nanotubes to alter the bioelectrical signatures of cells and develop a sensor based on alternating current pulses and light irradiation to differentiate between healthy and cancer cells. Molecular dynamics simulations reveal the interaction between carbon nanotubes and cancer cell membranes, resulting in a change in lipid bilayer structure and enhancing current. This cancer cell-specific method offers a promising route for early diagnosis and monitoring of cancer.
Article
Biochemical Research Methods
Mathew P. Martin, Martin E. M. Noble
Summary: This article evaluates methods for validating and prioritizing crystallographic fragment screening results. Through retrospective analysis of an ATAD2 screening campaign and other successful fragment screening projects, a "triangulation" approach is suggested to develop qualitative structure-activity relationships (SARs) as an alternative to on-scale biophysical, biochemical, and/or biological measurements.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2022)
Editorial Material
Oncology
David P. Lane, Chandra S. Verma
Summary: Mutant p53 proteins are found in various human cancers. In this study, Guiley and Shokat report on the development of compounds that can restore the function of Y220C mutant p53 protein by covalently binding to it.
Article
Pharmacology & Pharmacy
Vishnu Suresh Babu, Atish Kizhakeyil, Gagan Dudeja, Shyam S. Chaurasia, Veluchami Amutha Barathi, Stephane Heymans, Navin Kumar Verma, Rajamani Lakshminarayanan, Arkasubhra Ghosh
Summary: Host defense peptides, namely hyper-charged wholly cationic antimicrobial dodecapeptides (CAPs), demonstrated excellent bactericidal activities against pathogenic bacteria and exhibited potent anticancer properties against retinoblastoma cells. Two CAPs, HC3 and HC5, were found to induce apoptosis in retinoblastoma cells and showed synergistic effects when combined with the chemotherapeutic drug topotecan.
Article
Multidisciplinary Sciences
Yuezhen Xue, Boris San Luis, Regine J. Dress, Katzrin Binte Ahmad Murad, Florent Ginhoux, Nick Barker, David Lane
Summary: This study demonstrates that the proteasome inhibitor bortezomib stabilizes p53 in stem and progenitor cells in gastrointestinal and lymphoid tissues. The stabilization of p53 is observed in various hematopoietic stem and progenitor cells, as well as T cells and B cells. Understanding the regulation of p53 in these cells is important for developing strategies for cancer treatment and immunotherapy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Pharmacology & Pharmacy
Venkatesh Mayandi, Wen-Tyng Kang, Darren Shu Jeng Ting, Eunice Tze Leng Goh, Myoe Naing Lynn, Thet Tun Aung, Jamuna Vadivelu, Veluchamy Amutha Barathi, Anita Sook Yee Chan, Rajamani Lakshminarayanan
Summary: This study demonstrates that the combination of propranolol and antifungal drugs can enhance antifungal activity, particularly in combination with itraconazole. In vivo studies using a murine systemic candidemia model showed that the combination treatment resulted in decreased weight loss, lower kidney fungal burden, and reduced renal inflammation compared to monotherapy or no treatment. These findings suggest that propranolol can increase the efficacy of azoles against C. albicans, providing a new therapeutic strategy for invasive fungal infections.
Article
Chemistry, Multidisciplinary
Denise Lee, J. Shamita Naikar, Sophia S. Y. Chan, Maria Prisca Meivita, Lunna Li, Yaw Sing Tan, Natasa Bajalovic, Desmond K. Loke
Summary: This study investigates the control of membrane permeabilization of cancer cells using different numbers of electric-field pulses and explores the potential of few-volt nanosecond AC-stimulation with an increased number of pulse strategies for the development of next-generation low-power electroporation systems.
Article
Chemistry, Multidisciplinary
Sophia S. Y. Chan, Denise Lee, Maria Prisca Meivita, Lunna Li, Yaw Sing Tan, Natasa Bajalovic, Desmond K. Loke
Summary: The study developed a DC resistance sensor based on 2D molybdenum disulfide nanosheets for cancer cell-specific detection dependent on micro-changes in the cancer cell membrane. Atomistic molecular dynamics simulations were used to study the interaction between the nanosheets and cancer lipid bilayer systems, revealing that perturbations in the lipid bilayer can cause an increase in resistance. This method has a detection limit of around 3 x 10(3) cells and shows promise for early detection of cancerous cells and reducing the risk of cancer recurrence post-surgery.
NANOSCALE ADVANCES
(2021)
Review
Biochemistry & Molecular Biology
Quynh Ngoc Vu, Reginald Young, Haritha Krishna Sudhakar, Tianyi Gao, Tiancheng Huang, Yaw Sing Tan, Yu Heng Lau
Summary: Cyclisation is a common synthetic strategy for enhancing the therapeutic potential of peptide-based molecules. While there are extensive studies on peptide cyclisation for reinforcing regular secondary structures, there are remarkably few reports of cyclising peptides with irregular conformations. This review highlights successful examples of using cyclisation techniques to stabilise irregular conformations and discusses how design approaches can be informed by existing methods and computational techniques. Through this analysis, existing peptide cyclisation techniques can be adapted to address the challenge of stabilising irregularly structured binding motifs.
RSC MEDICINAL CHEMISTRY
(2021)
