Article
Biochemistry & Molecular Biology
Elix Alberto Dominguez-Mendoza, Yelzyn Galvan-Cipres, Josue Martinez-Miranda, Cristian Miranda-Gonzalez, Blanca Colin-Lozano, Emanuel Hernandez-Nunez, Gloria I. Hernandez-Bolio, Oscar Palomino-Hernandez, Gabriel Navarrete-Vazquez
Summary: Novel substituted phenylacetic, phenylpropanoic, and benzylidenethiazolidine-2,4-dione derivatives were designed based on a multitarget unified pharmacophore pattern for robust antidiabetic activity. The compounds shared four pharmacophore elements and displayed significant antihyperglycemic effects in diabetic mice, showing potential for favorable pharmacokinetic and toxicological profiles. Molecular dynamics simulations provided insights into the compounds' mechanisms of action and binding to AR.
Article
Pharmacology & Pharmacy
Md. Abdul Hye Khan, Sung Hee Hwang, Scott D. Barnett, Anna Stavniichuk, Wojciech K. Jankiewicz, Bruce D. Hammock, John D. Imig
Summary: The study showed that the dual modulator PTUPB does not treat hyperglycemia but effectively alleviates hypertension, diabetic nephropathy, hyperlipidemia, and liver injury in type 2 diabetic rats. The renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Shivani Jaiswal, Senthil Raja Ayyannan
Summary: We designed and synthesized a series of N-1 and C-3 substituted isatin derivatives and found that compound 11 exhibited outstanding FAAH inhibition properties. This compound showed nanomolar-level inhibition and had high blood-brain permeability and significant antioxidant activity.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Alessandro Papa, Ilaria Cursaro, Luca Pozzetti, Chiara Contri, Martina Cappello, Silvia Pasquini, Gabriele Carullo, Anna Ramunno, Sandra Gemma, Katia Varani, Stefania Butini, Giuseppe Campiani, Fabrizio Vincenzi
Summary: This study aimed to develop multitarget inhibitors for the endocannabinoid system and epigenetic machinery to achieve synergistic therapeutic effects in oxidative stress-related conditions. The first-in-class FAAH-HDAC multitarget inhibitors were designed, synthesized, and evaluated for their neuroprotective properties. Compound 4h showed balanced inhibitory activity against the selected targets and outperformed the standard antioxidant in vitro.
ARCHIV DER PHARMAZIE
(2023)
Article
Biochemistry & Molecular Biology
Mingfei Wu, Xingxing Zhu, Yilong Zhang, Min Wang, Tongtong Liu, Jianfei Han, Jun Li, Zeng Li
Summary: The study found that compounds 4d, 4e, and 7c exhibit strong antioxidant, anti-A β self-aggregation, and anti-neuroinflammatory activities. Additionally, compound 7c was able to inhibit the expression of iNOS and COX-2 proteins in BV2 cells.
CHEMICO-BIOLOGICAL INTERACTIONS
(2021)
Article
Chemistry, Medicinal
Tugce Gur Maz, Sumeyye Turanli, H. Burak Caliskan, Burcu Caliskan, Erden Banoglu
Summary: A series of novel piperazine urea derivatives with thiadiazole moieties were designed, synthesized, and investigated for their inhibition potential against human fatty acid amide hydrolase (hFAAH). The urea derivatives possessing p-chlorophenylthiadiazole and benzylpiperazine fragments were identified as effective inhibitors of hFAAH, with compounds containing 4-chlorobenzyl and 4-fluorobenzyl tails showing the highest activity.
ARCHIV DER PHARMAZIE
(2022)
Article
Chemistry, Medicinal
Shivani Jaiswal, Garima Gupta, Senthil R. Ayyannan
Summary: This study designed and synthesized a series of carbamate compounds and evaluated their dual FAAH-MAGL inhibition properties. Compound 2e, 3h, and 2i showed the strongest inhibitory effects. Enzyme kinetics experiments revealed that these compounds inhibit FAAH/MAGL in a mixed binding mode of covalent-reversible manner. Additionally, docking simulation experiments and ADMETox prediction studies provided useful information for further investigation.
ARCHIV DER PHARMAZIE
(2022)
Article
Biochemistry & Molecular Biology
Chaoling Chen, Weili Wang, Justin L. Poklis, Aron H. Lichtman, Joseph K. Ritter, Gaizun Hu, Dengpiao Xie, Ningjun Li
Summary: The study suggests that FAAH activation and the consequent reduction of AEA contribute to renal fibrogenesis, while FAAH inhibition protects against fibrogenesis in renal cells independently of CB receptors via the AEA-COX-2 pathway.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2022)
Article
Microbiology
Vinay Randhawa, Shivalika Pathania, Manoj Kumar
Summary: Nipah virus is an emerging paramyxovirus with no approved molecular therapeutics for human use. In this study, a sequential molecular docking and molecular dynamics approach was used to identify potential multitarget inhibitors against Nipah virus by targeting its attachment glycoprotein G, fusion glycoprotein, and nucleoprotein. Two phytochemical molecules, RASE0125 and CARS0358, were found to be distinct multitarget inhibitors, along with a chemical molecule, ND_nw_193. These compounds could be potential candidates for further antiviral studies and clinical treatment of Nipah virus.
Article
Biochemistry & Molecular Biology
Sanela Rajlic, Luise Surmann, Pia Zimmermann, Christina Katharina Weisheit, Laura Bindila, Hendrik Treede, Markus Velten, Andreas Daiber, Georg Daniel Duerr
Summary: Ischemic cardiomyopathy leads to inflammation and left ventricular dysfunction. Animal studies suggest that the endocannabinoid system may have cardioprotective effects, including cardiomyocyte adaptation, inflammation, and remodeling. This study investigates the potential cardioprotective effect of the endocannabinoid anandamide (AEA) after ischemia and reperfusion using FAAH (-/-) mice and suggests that increased endocannabinoids may have detrimental effects on cardiomyocyte survival due to PPAR-alpha activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Veterinary Sciences
Vikram Thakur, Mohammad Bashashati, Josue Enriquez, Munmun Chattopadhyay
Summary: This study assessed specific gastrointestinal symptoms in Type 1 diabetic mice and evaluated treatment options for this condition. The results showed that inhibiting endocannabinoid degradation may have a therapeutic effect on gastrointestinal dysmotility.
VETERINARY SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Raissa Alves da Conceicao, Natalia von Ranke, Luciana Azevedo, Daiana Franco, Nathalia Fonseca Nadur, Arthur Eugen Kummerle, Maria Leticia de C. Barbosa, Alessandra M. T. Souza
Summary: The complexity of Alzheimer's disease necessitates the development of multitarget-directed drugs. In this study, the chemical structure of the acetylcholinesterase inhibitor drug donepezil was modified to design new N-benzyl-piperidine derivatives as potential multitarget-direct inhibitors. In silico and in vitro methods were used to study the designed analogues, and the results showed that derivative 4a was the most potent inhibitor of both AChE and BuChE. This study highlights the potential of 4a as a novel multitarget-directed inhibitor.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Valerio Chiurchiu, Lucia Scipioni, Beatrice Arosio, Daniela Mari, Sergio Oddi, Mauro Maccarrone
Summary: Growing evidence suggests that the immune system plays a critical role in the pathogenesis and progression of Alzheimer's disease, with targeting peripheral immune mechanisms showing promise as therapeutic strategies. Research has found that in AD patients, there is significantly reduced expression of CB1 and CB2 in B-lymphocytes, and decreased CB2 and increased FAAH in monocytes. Pharmacological inactivation of FAAH in monocytes from AD patients can modulate immune responses by altering cytokine production.
Article
Biochemistry & Molecular Biology
Tiziana Genovese, Andrea Duranti, Ramona D'Amico, Roberta Fusco, Daniela Impellizzeri, Alessio Filippo Peritore, Rosalia Crupi, Enrico Gugliandolo, Salvatore Cuzzocrea, Rosanna Di Paola, Rosalba Siracusa, Marika Cordaro
Summary: Acute lung injury (ALI) is a lung disease characterized by severe inflammation without treatment. This study investigated the role of fatty acid amide hydrolase (FAAH) inhibition in an ALI mouse model and found that it could counteract the inflammatory response and histological changes caused by the disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Alessandro Deplano, Jessica Karlsson, Federica Moraca, Mona Svensson, Claudia Cristiano, Carmine Marco Morgillo, Christopher J. Fowler, Roberto Russo, Bruno Catalanotti, Valentina Onnis
Summary: The study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Jimin Wang, Erin Skeens, Pablo R. Arantes, Federica Maschietto, Brandon Allen, Gregory W. Kyro, George P. Lisi, Giulia Palermo, Victor S. Batista
Summary: This study demonstrates that Lys-to-Ala mutations in Cas9 protein increase substrate specificity by reducing the versatility of a loop region, which can adopt multiple conformations in the wild-type enzyme. The findings provide experimental and computational evidence that Lys-to-Ala substitutions decrease protein dynamics and increase stability.
Article
Biochemistry & Molecular Biology
Aakash Saha, Pablo R. Arantes, Giulia Palermo
Summary: This article reviews the role of molecular simulations in the CRISPR-Cas9 revolution, including studies on RNA binding, catalytic mechanism, off-target effects, etc. It reveals the dynamics and mechanism of CRISPR-Cas9, contributing to understanding its function and specificity.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Nicoletta Brindani, Federico Munaf, Andrea Menichetti, Elisa Donati, Michela Nigro, Giuliana Ottonello, Andrea Armirotti, Marco De Vivo
Summary: In this study, 17 new 1,4-benzopyrone derivatives were designed, synthesized, and characterized for their ability to inhibit the RdRp enzyme. Compounds 4, 5, and 8 showed promising activity in inhibiting RdRp with improved pharmacokinetics compared to initial hits and no cytotoxicity effects on normal cells (HEK-293). Compound 8 (ARN25592) was identified as the most promising inhibitor.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Federico Munafo, Michela Nigro, Nicoletta Brindani, Jacopo Manigrasso, Inacrist Geronimo, Giuliana Ottonello, Andrea Armirotti, Marco De Vivo
Summary: Pol eta plays a crucial role in allowing DNA replication and cell proliferation in cancer cells, even in the presence of chemotherapeutic drug-induced damages. Inhibiting Pol eta could potentially overcome drug resistance and enhance the effectiveness of platinum-containing drugs. This study reports the discovery of a new class of Pol n inhibitors, with compound 21 (ARN24964) showing the best inhibitory activity and synergistic effect with cisplatin in multiple cancer cell lines. Furthermore, ARN24964 possesses favorable drug-like properties, making it a promising candidate for further drug development efforts against drug resistance in cancer patients receiving platinum-containing drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Chemistry, Physical
Marco De Vivo
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Biochemistry & Molecular Biology
Anshuman Kumar, Pablo R. R. Arantes, Aakash Saha, Giulia Palermo, Bryan M. M. Wong
Summary: To overcome the computational challenges of large chemical systems, researchers used a GPU-enhanced DFTB approach on a massively parallelized cloud computing platform to efficiently calculate the thermodynamics and metadynamics of biochemical systems. The benchmark tests and extensions demonstrated that GPU-accelerated DFTB simulations are significantly faster and can predict the free-energy surfaces/thermodynamics of large biochemical systems effectively.
Article
Chemistry, Physical
Lukasz Nierzwicki, Mohd Ahsan, Giulia Palermo
Summary: This article discusses the role of ab-initio molecular dynamics (MD) in the CRISPR-Cas9 genome editing revolution, and how it provides insights into the enzymatic function and catalytic mechanism of the Cas9 enzyme. The use of ab-initio MD simulations and free-energy methods to study DNA cleavage and chemical bonds are explained. The importance of classical methods, such as constant pH MD simulations, is also discussed.
ELECTRONIC STRUCTURE
(2023)
Article
Chemistry, Medicinal
Annalisa Savardi, Andrea Patricelli Malizia, Marco De Vivo, Laura Cancedda, Marco Borgogno
Summary: Alterations in the expression of NKCC1 and KCC2 lead to imbalanced excitation/inhibition in the brain, which is observed in neurological disorders such as Down syndrome and autism. ARN23746, a selective NKCC1 inhibitor, shows promising results in rescuing cognitive impairment in Down syndrome mice and exhibits good safety and pharmacokinetic profiles, making it a solid candidate for clinical trial-enabling studies.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Chemistry, Medicinal
Bharath Raghavan, Mirko Paulikat, Katya Ahmad, Lara Callea, Andrea Rizzi, Emiliano Ippoliti, Davide Mandelli, Laura Bonati, Marco De Vivo, Paolo Carloni
Summary: Currently, in silico drug design in the initial stages of drug discovery can benefit from first-principle Quantum Mechanics/Molecular Mechanics (QM/MM) molecular dynamics (MD) simulations in explicit solvent, but many applications are limited by the short time scales that this approach can cover. The development of scalable first principle QM/MM MD interfaces that fully exploit current exascale machines is crucial in overcoming this problem and allowing for the study of ligand binding to protein with first principle accuracy. This study showcases the use of the Multiscale Modeling in Computational Chemistry (MiMiC) QM/MM framework, which demonstrates strong scaling and parallel efficiency of >70% up to >80,000 cores, making it a promising candidate for exascale applications.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Medicinal
Inacrist Geronimo, Pietro Vidossich, Marco De Vivo
Summary: A common and insidious DNA damage, 8-oxoguanine (8OG), is bypassed with low efficiency and high error rate by polymerases (Pols) during DNA replication. The molecular determinants of how 8OG affects Pols' efficiency remain unclear. This study discovered that 8OG adopts different conformations when bound to Pols compared to isolated DNA. Mutating Pol residues interacting with the 8OG phosphate group can regulate the conformation, suggesting its importance in Pol-mediated processing of damaged DNA.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Sebastian Franco-Ulloa, Laura Riccardi, Federico Rimembrana, Edwin Grottin, Mattia Pini, Marco De Vivo
Summary: Functionalized metal nanoparticles are macromolecular assemblies with tunable physicochemical properties, and molecular simulations can help explore their structural and dynamical features. This paper introduces a new webserver called NanoModeler CG, which can build and parameterize monolayer-protected metal nanoparticles at a coarse-grained resolution. The tool is demonstrated to reproduce experimental features and explain the phase transition of the nanoparticles.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Review
Chemistry, Physical
Souvik Sinha, Chinmai Pindi, Mohd Ahsan, Pablo R. Arantes, Giulia Palermo
Summary: This article reports the increasing role of computational biophysics in characterizing the mechanisms of gene machines, focusing on innovative applications of computational methods and their integration with structural and biophysical experiments. Advanced computational methods reveal the biophysical function that is unseen through experimental techniques, accomplishing the power of the computational microscope. Bridging the gap between experimentally obtained macroscopic observables and the molecular principles playing at the microscopic level is crucial for harnessing molecular machines for medical, pharmaceutical, and biotechnological purposes.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Sebastian Franco-Ulloa, Andrea Cesari, Laura Riccardi, Federico De Biasi, Daniele Rosa-Gastaldo, Fabrizio Mancin, Marco De Vivo, Federico Rastrelli
Summary: Nanoparticle-assisted nuclear magnetic resonance (NMR) chemosensing is a technique that uses monolayer-protected nanoparticles as supramolecular hosts to detect small molecules in complex mixtures. The structure-sensitivity relationships that determine the detection limits of this technique are still not well understood. This study combines NMR spectroscopy and atomistic molecular dynamics simulations to investigate the factors that affect the sensitivity of different NMR chemosensing experiments. The results show that the intensity of the observed signals is correlated with the spin-spin interactions between the analytes and the nanoparticles, as well as the analytes and the nanoparticles' solvation molecules.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2023)
Editorial Material
Chemistry, Multidisciplinary
Souvik Sinha, Mohd Ahsan, Giulia Palermo
Summary: Expanding the genetic code beyond natural amino acids is hindered by the challenge of incorporating non-natural building blocks within the ribosome. However, researchers have now identified the molecular determinants that enable efficient incorporation of these non-natural amino acids, leading to accelerated ribosomal synthesis.
Editorial Material
Chemistry, Physical
Aakash Saha, Chinmai Pindi, Giulia Palermo
Summary: CRISPR-Cas9, a major gene-editing tool, has been studied using cryo-electron microscopy to capture the pivotal structural features of Cas9 endonuclease during double-stranded DNA cleavages, laying the foundation for improved Cas9 engineering.