More Like this

1. Enolase Inhibitors as Early Lead Therapeutics against Trypanosoma brucei

   https://doi.org/10.3390/pathogens12111290  

   Roster, Colm P.; LaVigne, Danielle; Milanes, Jillian E.; Knight, Emily; Anderson, Heidi D.; Pizarro, Sabrina; Harding, Elijah M.; Morris, Meredith T.; Yan, Victoria C.; Pham, Cong-Dat; et al (November 2023, Pathogens)

   Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of −6.8 and −7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of −4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei, with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted. 

   more » « less
2. Exploring Cannabinoids as Potential Inhibitors of SARS-CoV-2 Papain-like Protease: Insights from Computational Analysis and Molecular Dynamics Simulations

   https://doi.org/10.3390/v16060878  

   Holmes, Jamie; Islam, Shahidul M; Milligan, Kimberly A (June 2024, Viruses)

   The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global COVID-19 pandemic, challenging healthcare systems worldwide. Effective therapeutic strategies against this novel coronavirus remain limited, underscoring the urgent need for innovative approaches. The present research investigates the potential of cannabis compounds as therapeutic agents against SARS-CoV-2 through their interaction with the virus’s papain-like protease (PLpro) protein, a crucial element in viral replication and immune evasion. Computational methods, including molecular docking and molecular dynamics (MD) simulations, were employed to screen cannabis compounds against PLpro and analyze their binding mechanisms and interaction patterns. The results showed cannabinoids with binding affinities ranging from −6.1 kcal/mol to −4.6 kcal/mol, forming interactions with PLpro. Notably, Cannabigerolic and Cannabidiolic acids exhibited strong binding contacts with critical residues in PLpro’s active region, indicating their potential as viral replication inhibitors. MD simulations revealed the dynamic behavior of cannabinoid–PLpro complexes, highlighting stable binding conformations and conformational changes over time. These findings shed light on the mechanisms underlying cannabis interaction with SARS-CoV-2 PLpro, aiding in the rational design of antiviral therapies. Future research will focus on experimental validation, optimizing binding affinity and selectivity, and preclinical assessments to develop effective treatments against COVID-19. 

   more » « less
3. Kinetic and Structural Aspects of Glycosaminoglycan–Monkeypox Virus Protein A29 Interactions Using Surface Plasmon Resonance

   https://doi.org/10.3390/molecules27185898  

   Shi, Deling; He, Peng; Song, Yuefan; Cheng, Shuihong; Linhardt, Robert J.; Dordick, Jonathan S.; Chi, Lianli; Zhang, Fuming (September 2022, Molecules)

   Monkeypox virus (MPXV), a member of the Orthopoxvirus genus, has begun to spread into many countries worldwide. While the prevalence of monkeypox in Central and Western Africa is well-known, the recent rise in the number of cases spread through intimate personal contact, particularly in the United States, poses a grave international threat. Previous studies have shown that cell-surface heparan sulfate (HS) is important for vaccinia virus (VACV) infection, particularly the binding of VACV A27, which appears to mediate the binding of virus to cellular HS. Some other glycosaminoglycans (GAGs) also bind to proteins on Orthopoxviruses. In this study, by using surface plasmon resonance, we demonstrated that MPXV A29 protein (a homolog of VACV A27) binds to GAGs including heparin and chondroitin sulfate/dermatan sulfate. The negative charges on GAGs are important for GAG–MPXV A29 interaction. GAG analogs, pentosan polysulfate and mucopolysaccharide polysulfate, show strong inhibition of MPXV A29–heparin interaction. A detailed understanding on the molecular interactions involved in this disease should accelerate the development of therapeutics and drugs for the treatment of MPXV. 

   more » « less
4. Chirality Effects on the Intrinsic Acidity of Isomeric Tripeptides Containing a D/L-Cysteine on the N-terminus: CAA and dCAA

   https://doi.org/10.1016/j.ijms.2025.117472  

   Wang, S; Buen, Z; Harvey, K R; Zhang, Y; Ren, J (May 2025, International journal of mass spectrometry)

   Laskin, J; Ouyang, Z (Ed.)

   Chirality effects on the intrinsic gas-phase acidity of oligopeptides have been studied using a pair of stereoisomeric tripeptides consisting of a D/L-cysteine (C) and two residues of alanine (A): CAA and dCAA, where the C-terminus is amidated. Mass spectrometry measurements through bracketing via collision-induced dissociation clearly show that CAA is a stronger gas-phase acid than dCAA. Quantitative values of the acidity were determined using the extended Cooks kinetic method. The resulting deprotonation enthalpy (∆acidH) for CAA is 326.2 kcal/mol (1364.7 kJ/mol) and for dCAA it is 326.8 kcal/mol (1367.6 kJ/mol). The corresponding gas-phase acidity (∆acidG) for CAA is 321.3 kcal/mol (1344.2 kJ/mol) and for dCAA it is 322.0 kcal/mol (1347.3 kJ/mol). Changing the N-terminal cysteine from the L-form to the D-form reduces the gas-phase acidity by about 0.6 kcal/mol (2.5 kJ/mol). Extensive conformational searches followed by quantum chemical calculations at the ωB97X-D/6-311+G(d,p) level of theory yielded a set of lowest energy conformations for each peptide species. Theoretical gas-phase acidities calculated using the Boltzmann averaged conformational contributions are in good agreement with the experimental data. The shift in the acidity is likely due to the conformational effect induced by D-cysteine, which increases the stability of the neutral dCAA, and hence reduces its acidity. A chirality change on a single amino acid can have a noticeable effect on the biochemical properties of peptides and proteins. 

   more » « less
5. In Silico Screening of Natural Flavonoids against 3-Chymotrypsin-like Protease of SARS-CoV-2 Using Machine Learning and Molecular Modeling

   https://doi.org/10.3390/molecules28248034  

   Cai, Lianjin; Han, Fengyang; Ji, Beihong; He, Xibing; Wang, Luxuan; Niu, Taoyu; Zhai, Jingchen; Wang, Junmei (December 2023, Molecules)

   The “Long-COVID syndrome” has posed significant challenges due to a lack of validated therapeutic options. We developed a novel multi-step virtual screening strategy to reliably identify inhibitors against 3-chymotrypsin-like protease of SARS-CoV-2 from abundant flavonoids, which represents a promising source of antiviral and immune-boosting nutrients. We identified 57 interacting residues as contributors to the protein-ligand binding pocket. Their energy interaction profiles constituted the input features for Machine Learning (ML) models. The consensus of 25 classifiers trained using various ML algorithms attained 93.9% accuracy and a 6.4% false-positive-rate. The consensus of 10 regression models for binding energy prediction also achieved a low root-mean-square error of 1.18 kcal/mol. We screened out 120 flavonoid hits first and retained 50 drug-like hits after predefined ADMET filtering to ensure bioavailability and safety profiles. Furthermore, molecular dynamics simulations prioritized nine bioactive flavonoids as promising anti-SARS-CoV-2 agents exhibiting both high structural stability (root-mean-square deviation < 5 Å for 218 ns) and low MM/PBSA binding free energy (<−6 kcal/mol). Among them, KB-2 (PubChem-CID, 14630497) and 9-O-Methylglyceofuran (PubChem-CID, 44257401) displayed excellent binding affinity and desirable pharmacokinetic capabilities. These compounds have great potential to serve as oral nutraceuticals with therapeutic and prophylactic properties as care strategies for patients with long-COVID syndrome. 

   more » « less