Review
Biochemistry & Molecular Biology
Raudah Lazim, Donghyuk Suh, Jai Woo Lee, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi
Summary: The presence of GPCR dimers has sparked research into their importance in disease pathogenesis and drug design, uncovering new signaling pathways and potential therapeutic targets. The increasing influence of computational methods in research is providing new avenues for understanding the functions and interactions of GPCRs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Buenemann, Peter Kolb
Summary: Researchers computationally describe alternative allosteric pockets in G-protein-coupled receptors, identifying nine previously untargeted sites for synthetic ligands. They further investigate the potential of modulating receptor function through ligand binding to these sites.
NATURE COMMUNICATIONS
(2022)
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)
Review
Biochemistry & Molecular Biology
Alexander O. Shpakov
Summary: Allosteric regulation plays a critical role in the functioning of GPCRs and their signaling pathways. The complexity of allosteric effects caused by various regulators determines the multiplicity and topology of allosteric sites in GPCRs. These sites are involved in the regulation of receptor activity, GPCR-complex formation, and endocytosis. They are also targets for synthetic allosteric regulators and modulators. The review provides an overview of the principles and mechanisms of GPCRs allosteric regulation, the diversity of allosteric sites, and the endogenous and synthetic allosteric regulators.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Article
Biochemistry & Molecular Biology
Dongchen An, Steve Peigneur, Jan Tytgat
Summary: The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. WIN55,212-2, a non-selective agonist of CB1 and CB2, activates CB1 and CB2 at low concentrations and blocks GIRK1/2 at high concentrations.
Article
Pharmacology & Pharmacy
Jyrki P. Kukkonen
Summary: Recent data indicates cooperative effects between identical orthosteric binding sites in a G-protein-coupled receptor dimer. A mathematical model was created to test this concept, showing that even a neutral receptor ligand can allosterically affect agonist binding through the orthosteric binding site.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Antonella Ciancetta, Amandeep Kaur Gill, Tianyi Ding, Dmitry S. Karlov, George Chalhoub, Peter J. McCormick, Irina G. Tikhonova
Summary: This study developed a probe confined dynamic mapping protocol to predict allosteric sites on GPCRs, demonstrating the advantage of specific probes derived from GPCR allosteric ligand structures over commonly used cosolvents in allosteric site mapping. The protocol was successfully validated retrospectively on selected receptors and prospectively on the D-2 dopamine receptor, confirming the prediction through subsequent mutagenesis. It provides a fast and efficient prediction of key amino acid residues surrounding allosteric sites in membrane proteins, aiding in the design of allosteric modulators based on protein structure.
ACS CENTRAL SCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Christina A. Brust, Matthew A. Swanson, Laura M. Bohn
Summary: The cannabinoid receptors CB1 and CB2 play important roles in various physiological processes and are potential drug targets. Recent advancements in structure biology have provided high-resolution structures of CB1 and CB2 receptors, which enhance our understanding of their structure and function. These structures will contribute to the development of future therapeutics targeting CB1 and CB2 receptors.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Article
Multidisciplinary Sciences
Vaithish Velazhahan, Ning Ma, Gaspar Pandy-Szekeres, Albert J. Kooistra, Yang Lee, David E. Gloriam, Nagarajan Vaidehi, Christopher G. Tate
Summary: GPCRs are divided into six classes, with structures of vertebrate GPCRs well understood but not of fungal class D GPCRs. This study reveals the structure of a class D GPCR in yeast and its coupling to G proteins, providing a template for the design of drugs to treat fungal diseases.
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Hae Gon Lee, Shinill Kang, Joon Sang Lee
Summary: Protein-protein interactions and their binding are crucial for biological metabolism. Understanding the interactions between IgG and natural immunoglobulin-binding ligands is essential for pharmaceutical science and biotechnology. This study analyzed the binding strengths of IgG-spA and IgG-spG complexes and identified the mechanisms enabling these bindings.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Cell Biology
Joshua D. Frenster, Hediye Erdjument-Bromage, Gabriele Stephan, Niklas Ravn-Boess, Shuai Wang, Wenke Liu, Devin Bready, Jordan Wilcox, Bjorn Kieslich, Manuel Jankovic, Caroline Wilde, Susanne Horn, Norbert Strater, Ines Liebscher, Torsten Schoneberg, David Fenyo, Thomas A. Neubert, Dimitris G. Placantonakis
Summary: This study identifies PTK7 as an extracellular binding partner of GPR133 in glioblastoma, and shows that PTK7 enhances GPR133 signaling by binding to the N-terminal fragment of GPR133. This interaction is potentially relevant to the pathogenesis of glioblastoma.
Article
Biochemistry & Molecular Biology
Liudi Zhang, Jesse I. Mobbs, Lauren T. May, Alisa Glukhova, David M. Thal
Summary: G-protein coupled receptors (GPCRs) are important therapeutic targets for human disease. Allosteric modulators, which target alternative binding sites, offer opportunities for new therapeutics.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Simona Daniele, Simona Saporiti, Stefano Capaldi, Deborah Pietrobono, Lara Russo, Uliano Guerrini, Tommaso Laurenzi, Elham Ataie Kachoie, Luca Palazzolo, Vincenzo Russo, Maria Pia Abbracchio, Ivano Eberini, Maria Letizia Trincavelli
Summary: GPR17, a key regulator of myelination, is activated by endogenous ligands and pro-inflammatory molecules. This study investigates the structural and functional interactions between GPR17 and chemokine receptors CXCR2 and CXCR4. The results show that these receptors can form heterodimers and modulate intracellular cAMP levels. This cross-talk between receptors could impact the neuroinflammatory environment associated with demyelinating events.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Mrinalkanti Kundu, Aditi Dutta, Kuldeep K. Roy, Sajal K. Mal, Shouvik Karmakar, Aritra Mandal, Susanta K. Mondal, Sanjay Kumar, Soumya Saha, Subhankar Pradhan, Ratul Sarkar, Monali Chakrabarti, Pradip K. Malik, Manish Banerjee
Summary: Malaria remains a significant public health problem, and the emergence and spread of resistance to artemisinin-based combination therapies pose a threat. Researchers have used docking studies and pharmacokinetic studies to identify a potential new imidazopyridine compound with anti-malarial activity. In vitro and in vivo experiments have shown promising results for this compound.
CHEMICAL BIOLOGY & DRUG DESIGN
(2023)
Article
Chemistry, Medicinal
Reem A. Alkhodier, Sushil K. Mishra, Robert J. Doerksen, David A. Colby
Summary: Glycosylated natural products display biological activity but are deglycosylated by metabolic processes. CF2-derivatives of natural products are challenging to synthesize. Difluorinated molecules have unique conformational behavior due to changes in the glycosidic linkage. The site of glycosylation and substitution pattern on the flavonoid determine the conformational properties. Docking study showed potential for flavonoid-CF2-glycosides to retain a similar binding pose as the parent O-glycoside.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Pankaj Pandey, Mallika Kumarihamy, Krishna Chaturvedi, Mohamed A. M. Ibrahim, Janet A. Lambert, Murrell Godfrey, Robert J. Doerksen, Ilias Muhammad
Summary: Magnolia grandiflora L. is a plant with significant medicinal importance, especially its flowers and seeds. The extract of n-hexane seeds showed binding affinity to both CB1 and CB2 cannabinoid receptors. Compounds 1-3, including 4-O-methylhonokiol, had higher binding affinity to cannabinoid receptors compared to opioid receptors. Molecular docking studies revealed the importance of hydroxyl groups in the neolignan molecules for binding to CB1R and CB2R receptors.
Article
Biochemistry & Molecular Biology
Nicholas S. Akins, Mohammed F. Salahuddin, Pankaj Pandey, Seong Jong Kim, Fakhri Mahdi, Md Imdadul H. Khan, Emaya M. Moss, Charlie J. Worth, Madeline M. Keane, Amar G. Chittiboyina, Robert J. Doerksen, Jason J. Paris, Hoang V. Le
Summary: The KOR is involved in the regulation of reward and mood, and drug abuse increases its activation. Long-acting KOR antagonists have been shown to alleviate withdrawal symptoms, but their use in humans comes with safety concerns. This study found that a short-acting KOR antagonist showed efficacy in reducing withdrawal behavior in mice, and computational studies provided insights for the design of future antagonists.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Chemistry, Medicinal
Amar G. G. Chittiboyina, Zulfiqar Ali, Bharathi Avula, Shabana I. I. Khan, Tahir M. M. Mir, Jin Zhang, Fadime Aydogan, Fazila Zulfiqar, Natascha Techen, Iffat Parveen, Pankaj Pandey, Sebastian J. J. Adams, Yan-Hong Wang, Jianping Zhao, Gailen D. D. Marshall, Nirmal D. D. Pugh, Ikhlas A. A. Khan
Summary: The French Lentil & Leek Crumbles frozen food product has been recalled due to gastrointestinal issues, with 393 adverse illness complaints and 133 hospitalizations reported. The Tara protein flour ingredient is believed to be the cause. A compound called (S)-(-)-baikiainin tara was identified as a compound of interest, with potential implications on liver health.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Article
Chemistry, Medicinal
Jongmin Ahn, Cristina Avonto, Pankaj Pandey, Shabana I. Khan, Ikhlas A. Khan, David W. Roberts, Amar G. Chittiboyina
Summary: Structurally similar phytochemical compounds can have different skin sensitization responses. Eugenol and isoeugenol, found in essential oils and used as fragrance ingredients, are both skin sensitizers, with isoeugenol being stronger. The mechanism for isoeugenol's increased skin response remains unclear. The recent identification of syn-7,4'-oxyneolignans as potential skin sensitizers has renewed interest in understanding the mechanisms involved. Kinetic NMR spectroscopic and computational studies provide evidence for the preferential stereoselectivity of syn-7,4'-oxyneolignans and propose a rationale for isoeugenol's strong skin sensitization.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Article
Chemistry, Medicinal
Caroline V. L. Moreira, Ana Luiza G. Faria, Daiany P. B. Silva, Paulo Cesar Ghedini, Jose Luis Rodriges Martins, Adam W. Keasling, Jordan K. Zjawiony, Pankaj Pandey, Robert J. Doerksen, Hamilton B. Napolitano, Fabio F. da Rocha, Elson A. Costa, James O. Fajemiroye
Summary: The study evaluated the effects and possible mechanisms of the C(22)-fused-heteroaromatic analogue of Salvinorin A, known as P-3l, in mice nociception and anxiety models. P-3l showed potential as an analgesic and anxiolytic agent without significant adverse effects on organ weight or biochemical parameters. The effects of P-3l were mediated through opioid receptors, particularly mu and kappa receptors, as well as benzodiazepine binding sites.
Article
Pharmacology & Pharmacy
Anitha Police, Vijay Kumar Shankar, Pankaj Pandey, Srinath Rangappa, Robert J. Doerksen, S. Narasimha Murthy
Summary: Peripheral neuropathy (PN) is a condition characterized by peripheral nerve damage leading to severe pain. The current treatments for PN have either psychotropic side effects or are not effective enough. This study aims to find a safe inhibitor of the fatty acid amide hydrolase enzyme (FAAH) and develop a topical gel formulation to deliver anandamide, an endocannabinoid that relieves PN pain. The results showed that silymarin constituents, particularly silybin, demonstrated significant FAAH inhibition potential and increased the half-life of anandamide. The developed gel formulation increased the permeation of anandamide and silybin, resulting in a significant increase in pain threshold in rat models of PN.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2023)
Article
Biochemistry & Molecular Biology
William M. M. Neal, Pankaj Pandey, Shabana I. I. Khan, Ikhlas A. A. Khan, Amar G. G. Chittiboyina
Summary: This study developed multiple QSAR models using diverse PXR ligands, which can accurately predict the activity of toxic substances and dietary supplements. These computational approaches reduce the need for animal experiments and aid in regulatory decision-making.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Kuldeep K. Roy, Deeti Jyothi, Udita Paul, Soumi Sukla
Summary: Currently, there is no drug available for the treatment of mosquito-borne dengue. This study discovered and validated two novel non-nucleoside classes of small molecules that inhibit the RdRp domain in the NS5 protein of the dengue virus. Through docking, binding free-energy studies, and molecular dynamics simulation, the researchers identified six structurally distinct compounds from a commercial database and found two active compounds, KKR-D-02 and KKR-D-03, that showed significant reductions in DENV copy number in vitro. These compounds provide potential scaffolds for the development of new candidate molecules to intervene in dengue.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Nandan Sarkar, Pukar Khanal, Ravi Rawat, Yadu Nandan Dey, Kuldeep K. Roy
Summary: This study evaluates the impact of Perovskia abrotanoides and its active metabolites on strains of Mycobacterium tuberculosis. It reveals the significant antimycobacterial potential of P. abrotanoides and identifies rosmarinic acid and rosmarinic acid methyl ester as potent molecules against drug-resistant tuberculosis strains. The study also predicts and confirms specific targets for these molecules, suggesting their role in antimycobacterial activities.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Plant Sciences
Pradeep Paudel, Pankaj Pandey, Jason J. Paris, Nicole M. Ashpole, Fakhri Mahdi, Jun-Mian Tian, Joseph Lee, Mei Wang, Min Xu, Amar G. Chittiboyina, Ikhlas A. Khan, Samir A. Ross, Xing-Cong Li
Summary: Bioassay-guided fractionation of Santalum album essential oil led to the identification of α-santalol (1) and β-santalol (2) as new chemotypes of CB2 ligands. Nine structurally new derivatives were synthesized to find more selective and potent CB2 ligands. Compound 4e showed high affinity for CB2 receptor and no binding activity for CB1 receptor. Molecular docking and dynamics simulation confirmed the stability of the complex and provided insights for designing more potent and selective α-santalol-based CB2 ligands.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Biochemistry & Molecular Biology
Priyanka Samanta, Sushil K. Mishra, Vitor H. Pomin, Robert J. Doerksen
Summary: This study conducted a computational analysis on the binding of four oligosaccharide building blocks from novel marine sulfated glycans to the receptor-binding domain of SARS-CoV-2. It identified two binding sites and revealed the key structural features and interactions driving ligand binding. This study provided important structural information for the development of these novel glycans as potential therapeutics.
Article
Chemistry, Medicinal
Tomayo Berida, Samuel R. Mckee, Shamba Chatterjee, Destinee L. Manning, Wei Li, Pankaj Pandey, Siddharth Kaushal Tripathi, Yassin Mreyoud, Asya Smirnov, Robert J. Doerksen, Mary Jackson, Christian Ducho, Christina L. Stallings, Sudeshna Roy
Summary: The increase in multidrug-resistant cases of tuberculosis highlights the urgency of developing new treatment strategies. In this study, a series of compounds containing a 3-thio-1,2,4-triazole moiety were discovered and synthesized. These compounds exhibited inhibitory activity against Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies identified several potent analogs with low micromolar to nanomolar inhibitory activity against Mtb. These potent analogs showed no cytotoxicity in mammalian cells and were bactericidal against Mtb during infection of macrophages. Further investigations into the mechanism of action revealed potential metabolic liabilities for optimization. The findings suggest the potential of these compounds as a new class of 1,2,4-triazole compounds for tuberculosis treatment.
ACS INFECTIOUS DISEASES
(2023)
Article
Biochemistry & Molecular Biology
Bedabrata Ray, Kuldeep K. Roy
Summary: This study investigates the flexibility and stability of the binding site of Q203 in the Mtb cytochrome bcc complex using molecular dynamics simulation and free energy analysis. The study reveals multiple direct and indirect interactions and emphasizes the importance of certain residues. The primary source of the net binding free energy is found to be electrostatic energy. Overall, this study provides key insights for structure-based drug design and optimization.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)