Article
Multidisciplinary Sciences
Ruben Cloete, Mohd Shahbaaz, Melanie Grobbelaar, Samantha L. Sampson, Alan Christoffels
Summary: Nicotinamide-nucleotide adenylyl transferase (Rv2421c) has been identified as a potential drug target for Mycobacterium tuberculosis, and through structure-based virtual screening, novel compounds with high binding affinities and inhibitory properties have been discovered, particularly Novobiocin sodium salt. This study demonstrates the potential of Novobiocin and its derivatives, such as Coumermycin, as alternative treatments for tuberculosis.
Article
Biochemistry & Molecular Biology
Gabriele Minazzato, Elisa Marangoni, Carlo Fortunato, Riccardo Petrelli, Loredana Cappellacci, Fabio Del Bello, Leonardo Sorci, Massimiliano Gasparrini, Francesco Piacente, Santina Bruzzone, Nadia Raffaelli
Summary: Maintaining an adequate NAD(+) pool is crucial for cell survival, especially in tumor cells. Inhibition of NAD(+) biosynthesis through targeting enzymes such as NAMPT and NAPRT is considered a promising therapeutic strategy. A new continuous coupled fluorometric assay was developed to screen NAPRT inhibitors by measuring NADH formation. Several compounds were identified as NAPRT inhibitors and were shown to sensitize cancer cells to NAMPT inhibition, decreasing viability and intracellular NAD(+) levels.
Article
Multidisciplinary Sciences
Xueying Wang, Yanbin Feng, Xiaojia Guo, Qian Wang, Siyang Ning, Qing Li, Junting Wang, Lei Wang, Zongbao K. Zhao
Summary: Nicotinamide cytosine dinucleotide (NCD) is a non-natural cofactor that can be used to mediate redox transformations, and the authors have developed an NCD synthetase for intracellular NCD production.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Olamide Jeje, Reabetswe Maake, Ruan van Deventer, Veruschka Esau, Emmanuel Amarachi Iwuchukwu, Vanessa Meyer, Thandeka Khoza, Ikechukwu Achilonu
Summary: The threat of drug-resistant Klebsiella pneumoniae calls for the identification of new targets and development of effective antibacterial agents. This study focuses on nicotinate nucleotide adenylyltransferase (NNAT) as a potential target for antibacterial development. Experimental and computational approaches were used to analyze the structure of KpNNAT and its interaction with divalent cations. The results provide insights into the dynamics of ATP binding and the impact of divalent cations on KpNNAT activity. This study serves as a basis for future research on structure-based inhibitors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Cecilia Baldassarri, Gianfabio Giorgioni, Alessandro Piergentili, Wilma Quaglia, Stefano Fontana, Valerio Mammoli, Gabriele Minazzato, Elisa Marangoni, Massimiliano Gasparrini, Leonardo Sorci, Nadia Raffaelli, Loredana Cappellacci, Riccardo Petrelli, Fabio Del Bello
Summary: The inhibition of NAD biosynthesis is a potential therapeutic approach against cancer, while boosting NAD biosynthesis is relevant for neurodegeneration and metabolic diseases. Targeting NAMPT and NAPRT enzymes that regulate NAD biosynthesis has shown promise. In this study, new NAPRT modulators were identified as potential activators or inhibitors, with compound 18 showing good pharmacokinetic properties and behaving as an inhibitor towards NA and PRPP. Docking studies were performed to understand the structural basis, and a preliminary pharmacophore model shed light on the transition from inhibitors to activators.
Article
Biochemical Research Methods
Yan Liu, Chengting Luo, Ting Li, Wenhao Zhang, Zhaoyun Zong, Xiaohui Liu, Haiteng Deng
Summary: The study demonstrates that NMNH is a potent enhancer of NAD(+) and suppresses glycolysis, the TCA cycle, and cell growth. NMNH, produced through a chemical method, is more effective than NMN in increasing NAD(+) levels in vivo and in vitro, mediated by NMNAT.
JOURNAL OF PROTEOME RESEARCH
(2021)
Article
Multidisciplinary Sciences
Karen Almeida, Lisbeth Avalos-Irving, Steven Berardinelli, Kristen Chauvin, Silvia Yanez
Summary: Nicotinamide adenine dinucleotide (NAD) is a crucial molecule involved in cellular metabolism, human health, aging, and diseases. NAD functions as an electron storage molecule and can be cleaved into nicotinamide and Adenine diphosphate ribose. Various pathways are responsible for NAD biosynthesis to maintain cellular homeostasis. This study identifies novel activators of Nicotinamide PhosphribosylTransferase (NAMPT) through virtual compound screening and biochemical assays.
Article
Biology
Shengyu Feng, Liuling Guo, Hao Wang, Shanshan Yang, Hailiang Liu
Summary: The PncA gene in microbiota plays an important role in regulating NAD(+) synthesis in the host, thereby providing a potential target for modulating host NAD(+) levels.
COMMUNICATIONS BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Vitor Mendes, Simon R. Green, Joanna C. Evans, Jeannine Hess, Michal Blaszczyk, Christina Spry, Owain Bryant, James Cory-Wright, Daniel S-H Chan, Pedro H. M. Torres, Zhe Wang, Navid Nahiyaan, Sandra O'Neill, Sebastian Damerow, John Post, Tracy Bayliss, Sasha L. Lynch, Anthony G. Coyne, Peter C. Ray, Chris Abell, Kyu Y. Rhee, Helena I. M. Boshoff, Clifton E. Barry, Valerie Mizrahi, Paul G. Wyatt, Tom L. Blundell
Summary: Coenzyme A (CoA) is a crucial factor in various metabolic pathways and cellular processes, particularly in prokaryotes such as Mycobacterium tuberculosis. The biosynthesis of CoA involves five steps, with the second and third steps catalyzed by a bifunctional protein CoaBC in most prokaryotes. The researchers identified inhibitors of M. tuberculosis CoaB through a high-throughput screen and discovered a cryptic allosteric binding site within the enzyme.
NATURE COMMUNICATIONS
(2021)
Review
Cell Biology
Xin Yong, Lejiao Mao, Xiaofei Shen, Zhen Zhang, Daniel D. Billadeau, Da Jia
Summary: Endosomes are crucial cellular stations for protein trafficking, where proteins can be degraded or recycled to different cellular destinations. Recent studies have shown that pathogens like bacteria and viruses exploit host endosomal recycling pathways for their survival and replication. This manipulation of host signaling pathways by pathogens deepens our understanding of the molecular intricacies regulating endosomal trafficking.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Infectious Diseases
Martin Vestergaard, Dirk Bald, Hanne Ingmer
Summary: The ATP synthase plays a crucial role in bacteria metabolism and viability. The dependence on ATP synthase varies among different bacterial pathogens. Currently, there are approved ATP synthase inhibitors for treating tuberculosis, but no inhibitors are available for non-mycobacterial pathogens.
JOURNAL OF GLOBAL ANTIMICROBIAL RESISTANCE
(2022)
Article
Multidisciplinary Sciences
Bjoern Klabunde, Andre Wesener, Wilhelm Bertrams, Isabell Beinborn, Nicole Paczia, Kristin Surmann, Sascha Blankenburg, Jochen Wilhelm, Javier Serrania, Kevin Knoops, Eslam M. Elsayed, Katrin Laakmann, Anna Lena Jung, Andreas Kirschbaum, Sven Hammerschmidt, Belal Alshaar, Nicolas Gisch, Mobarak Abu Mraheil, Anke Becker, Uwe Voelker, Evelyn Vollmeister, Birke J. Benedikter, Bernd Schmeck
Summary: This study reveals that the dysregulation of the NAD(+) salvage pathway upon Streptococcus pneumoniae infection promotes bacterial replication, while NAD(+) treatment inhibits its growth. Additionally, increasing NAD(+) production reduces bacterial replication and exerts antibacterial effects by affecting bacterial metabolism.
NATURE COMMUNICATIONS
(2023)
Review
Biotechnology & Applied Microbiology
Ursula Theuretzbacher, Benjamin Blasco, Maelle Duffey, Laura J. V. Piddock
Summary: Advances in genomics, systems biology, protein structure determination, and artificial intelligence provide new opportunities for target-based antibacterial drug discovery. Multiple criteria, including target essentiality, conservation, homology with human genes, and drug-like binding potential, need to be considered in selecting a suitable target. Subcellular location and the risk of drug resistance also play important roles in the process. This review highlights promising targets and inhibitors for Gram-negative bacteria and lessons learned from past drug discovery programs.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Review
Biochemistry & Molecular Biology
Palmiro Poltronieri, Valeria Mezzolla, Ammad Ahmad Farooqi, Maria Di Girolamo
Summary: Mitochondrial dysfunction and oxidative stress are common features in many human disorders, with NAD(+) playing a crucial role in maintaining mitochondrial and cell functions. Supplementing NAD(+) cycling intermediates and inhibiting sirtuins and ADP-ribosyl transferases may offer a potential therapeutic approach for treating cancer and neurodegenerative diseases.
CURRENT MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Yara El-Dash, Nadia A. Khalil, Eman M. Ahmed, Marwa S. A. Hassan
Summary: Two novel series of compounds derived from nicotinic acid were synthesized and evaluated for their inhibitory activity against COX-1 and COX-2, showing high potency and selectivity towards COX-2 inhibition. The most potent compound exhibited strong in vivo anti-inflammatory activity and potential influence on inflammatory cytokines, suggesting promising anti-inflammatory properties. Molecular docking studies further supported their remarkable COX-2 inhibitory activity compared to celecoxib.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Massimiliano Gasparrini, Francesca Mazzola, Massimiliano Cuccioloni, Leonardo Sorci, Valentina Audrito, Federica Zamporlini, Carlo Fortunato, Adolfo Amici, Michele Cianci, Silvia Deaglio, Mauro Angeletti, Nadia Raffaelli
Summary: This study investigated the interaction between the enzyme NAMPT and the receptor TLR4, and found that specific regions of NAMPT play a key role in TLR4 binding and impact the initiation of inflammatory response and the signaling pathway.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Anmol Kumar, Poonam Pandey, Payal Chatterjee, Alexander D. Jr Jr MacKerell
Summary: The Drude polarizable force field captures electronic polarization effects and is useful for simulating biomolecules and other molecules. Deep neural network models can accurately predict molecular dipole moments and polarizabilities.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Multidisciplinary
Abhishek A. Kognole, Jumin Lee, Sang-Jun Park, Sunhwan Jo, Payal Chatterjee, Justin A. Lemkul, Jing Huang, Alexander D. MacKerell, Wonpil Im
Summary: The Drude Prepper tool has been developed in CHARMM-GUI to facilitate the use of polarizable FF based on the classic Drude oscillator model. It allows for easy construction of Drude FF-based PSF and generation of input for MD simulations using various simulation packages. The stability and effectiveness of the Drude Prepper protocol and inputs have been demonstrated through validation with a variety of heterogeneous systems.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2022)
Article
Chemistry, Physical
Adam T. Green, Amanda J. Pickard, Rongzhong Li, Alexander D. MacKerell, Ulrich Bierbach, Samuel S. Cho
Summary: This study uses circular dichroism spectroscopy to show the parallel topologies of two putative ribosomal G-quadruplex sequences, and validates and refines the modeled structures using molecular dynamics simulations. The results provide a structural foundation for understanding G-quadruplex functions and designing novel chemotherapeutics.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Review
Chemistry, Multidisciplinary
Himanshu Goel, Anthony Hazel, Wenbo Yu, Sunhwan Jo, Alexander D. MacKerell
Summary: SILCS utilizes molecular simulation to obtain functional group affinity patterns for drug discovery, allowing for identification of novel ligand binding pockets, prediction of protein-ligand binding affinities, and other applications in computer-aided drug design. It represents a comprehensive approach to improve drug development processes through accuracy and throughput enhancements.
NEW JOURNAL OF CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Emiliano Laudadio, Giovanna Mobbili, Leonardo Sorci, Roberta Galeazzi, Cristina Minnelli
Summary: The discovery of mutations within the kinase domain of the EGFR gene has revolutionized targeted therapy for NSCLC. However, the impact of these mutations on the conformation and stability of EGFR-ATP complexes is still not fully understood. In this study, we used dynamic docking simulations to investigate the effect of mutations on the Michaelis-Menten constant and observed a correlation with ATP affinities. Additionally, we found that ATP binding is the first step in promoting the conformational shift to the active state and highlighted the contribution of water hydrogen bond and water-bridge networks in the modulation of ATP affinity. These findings provide valuable insights for cancer therapy and personalized medicine development.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Gabriele Minazzato, Elisa Marangoni, Carlo Fortunato, Riccardo Petrelli, Loredana Cappellacci, Fabio Del Bello, Leonardo Sorci, Massimiliano Gasparrini, Francesco Piacente, Santina Bruzzone, Nadia Raffaelli
Summary: Maintaining an adequate NAD(+) pool is crucial for cell survival, especially in tumor cells. Inhibition of NAD(+) biosynthesis through targeting enzymes such as NAMPT and NAPRT is considered a promising therapeutic strategy. A new continuous coupled fluorometric assay was developed to screen NAPRT inhibitors by measuring NADH formation. Several compounds were identified as NAPRT inhibitors and were shown to sensitize cancer cells to NAMPT inhibition, decreasing viability and intracellular NAD(+) levels.
Article
Chemistry, Medicinal
Cecilia Baldassarri, Gianfabio Giorgioni, Alessandro Piergentili, Wilma Quaglia, Stefano Fontana, Valerio Mammoli, Gabriele Minazzato, Elisa Marangoni, Massimiliano Gasparrini, Leonardo Sorci, Nadia Raffaelli, Loredana Cappellacci, Riccardo Petrelli, Fabio Del Bello
Summary: The inhibition of NAD biosynthesis is a potential therapeutic approach against cancer, while boosting NAD biosynthesis is relevant for neurodegeneration and metabolic diseases. Targeting NAMPT and NAPRT enzymes that regulate NAD biosynthesis has shown promise. In this study, new NAPRT modulators were identified as potential activators or inhibitors, with compound 18 showing good pharmacokinetic properties and behaving as an inhibitor towards NA and PRPP. Docking studies were performed to understand the structural basis, and a preliminary pharmacophore model shed light on the transition from inhibitors to activators.
Article
Chemistry, Physical
Wenbo Yu, David J. Weber, Alexander D. MacKerell
Summary: Covalent drug design plays a significant role in drug discovery by forming a covalent bond with targeted residues, leading to a more effective therapeutic approach. Computational methods can identify reactive residues, test potential reactivities, and predict noncovalent contributions to binding. SILCS, a functional group mapping approach, considers protein flexibility, functional group, and protein desolvation along with functional group-protein interactions. SILCS-Covalent, an integrated workflow, can qualitatively and quantitatively inform covalent drug discovery.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Physical
Yalun Yu, Richard M. Venable, Jonathan Thirman, Payal Chatterjee, Anmol Kumar, Richard W. Pastor, Benoit Roux, Alexander D. MacKerell Jr, Jeffery B. Klauda
Summary: Accurate empirical force fields of lipid molecules are crucial for molecular dynamics simulations of various lipid systems and heterogeneous systems. The polarizable Drude force field has been optimized in this study to improve its accuracy in simulating pure bilayers and membranes. By using both experimental and quantum mechanical data, the optimized force field shows good agreement with a range of experimental observables. The polarizable Drude2023 force field is anticipated to advance our understanding of electronic polarization in lipid systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Mingtian Zhao, Abhishek A. Kognole, Sunhwan Jo, Aoxiang Tao, Anthony Hazel, Alexander D. MacKerell Jr
Summary: In this study, the sampling efficiency of the GCMC method was improved by applying known cavity-bias and configurational-bias algorithms on GPU architecture. The method was parallelized using CUDA and OpenCL, resulting in simultaneous sampling of a large number of configurations during insertion attempts. The partitioning scheme allowed for simultaneous insertion attempts for large systems, significantly improving efficiency. The algorithm was shown to be useful in the application of the site-identification by ligand competitive saturation (SILCS) co-solvent sampling approach for the protein CDK2.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Asuka A. Orr, Aoxiang Tao, Olgun Guvench, Alexander D. MacKerell
Summary: Protein-based therapeutics often face challenges of protein aggregation and high solution viscosity due to high concentrations of active protein. The charge of a protein, affected by its environment, plays a significant role in these solution behaviors. This study presents a structure-based approach called SILCS-Biologics, which predicts the effective charge of proteins by considering the competition between ions and the presence of buffers.
MOLECULAR PHARMACEUTICS
(2023)
Article
Chemistry, Multidisciplinary
Mert Y. Sengul, Alexander D. MacKerell
Summary: Metal ions, particularly Mg2+, play a role in stabilizing RNA's tertiary structures. However, the atomic-level mechanisms underlying this process are not fully understood. In this study, computational techniques were combined to investigate the specific interactions between Mg2+ ions and RNA, particularly in the pseudoknot structure of the Twister ribozyme.
Article
Chemistry, Multidisciplinary
Himanshu Goel, Wenbo Yu, Alexander D. MacKerell
Summary: This article presents the application of structure- and ligand-based approaches in simulating and predicting hERG drug liability. By combining the SILCS method with physicochemical properties, predictive models for hERG blockade were developed, resulting in improved predictability and aiding in rational drug design to minimize hERG risk.
CHEMISTRY-SWITZERLAND
(2022)
Article
Chemistry, Multidisciplinary
Mert Y. Sengul, Alexander D. MacKerell
Summary: The presence of polarizability in the force field improves the stability of RNA hairpin structures and leads to variations in dipole moments and ion distribution. Molecular dynamics simulations play a crucial role in modeling biomolecular systems, and the treatment of electrostatic interactions in the force field strongly affects simulation accuracy. In this study, the impact of polarization on structural properties, dipole moment distributions, and cation interactions in RNA hairpin systems is investigated using polarizable and non-polarizable nucleic acid force fields.
JOURNAL OF COMPUTATIONAL BIOPHYSICS AND CHEMISTRY
(2022)
