binding affinity
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2022 ◽  
Vol 12 ◽  
Chongming Jiang ◽  
Evelien Schaafsma ◽  
Wei Hong ◽  
Yanding Zhao ◽  
Ken Zhu ◽  

BackgroundNeoantigens are presented on the cancer cell surface by peptide-restricted human leukocyte antigen (HLA) proteins and can subsequently activate cognate T cells. It has been hypothesized that the observed somatic mutations in tumors are shaped by immunosurveillance.MethodsWe investigated all somatic mutations identified in The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) samples. By applying a computational algorithm, we calculated the binding affinity of the resulting neo-peptides and their corresponding wild-type peptides with the major histocompatibility complex (MHC) Class I complex. We then examined the relationship between binding affinity alterations and mutation frequency.ResultsOur results show that neoantigens derived from recurrent mutations tend to have lower binding affinities with the MHC Class I complex compared to peptides from non-recurrent mutations. Tumor samples harboring recurrent SKCM mutations exhibited lower immune infiltration levels, indicating a relatively colder immune microenvironment.ConclusionsThese results suggested that the occurrences of somatic mutations in melanoma have been shaped by immunosurveillance. Mutations that lead to neoantigens with high MHC class I binding affinity are more likely to be eliminated and thus are less likely to be present in tumors.

2022 ◽  
Vol 9 ◽  
Ponnusamy Packialakshmi ◽  
Perumal Gobinath ◽  
Daoud Ali ◽  
Saud Alarifi ◽  
Raman Gurusamy ◽  

In this work, we synthesize the sulfonated Schiff bases of the chitosan derivatives 2a-2j without the use of a catalyst in two moderately straightforward steps with good yield within a short reaction time. The morphology and chemical structure of chitosan derivatives were investigated using FT-IR, NMR (1H—13C), XRD, and SEM. Furthermore, our chitosan derivatives were tested for their anticancer activity against the MCF-7 cancer cell line, and doxorubicin was used as a standard. In addition, the normal cell lines of the breast cancer cell MCF-10A, and of the lung cell MRC-5 were tested. Compound 2 h, with a GI50 value of 0.02 µM for MCF-7, is highly active compared with the standard doxorubicin and other compounds. The synthesized compounds 2a-2j exhibit low cytotoxicity, with IC50 > 100 μg/ml, against normal cell lines MCF-10A, MRC-5. We also provide the results of an in-silico study involving the Methoxsalen protein (1Z11). Compound 2h exhibits a higher binding affinity for 1Z11 protein (−5.9 kcal/mol) and a lower binding affinity for Doxorubicin (−5.3 kcal/mol) than certain other compounds. As a result of the aforementioned findings, the use of compound 2h has an anticancer drug will be researched in the future.

mAbs ◽  
2022 ◽  
Vol 14 (1) ◽  
Bo-Seong Jeong ◽  
Jeong Seok Cha ◽  
Insu Hwang ◽  
Uijin Kim ◽  
Jared Adolf-Bryfogle ◽  

2022 ◽  
Rahul Kaushik ◽  
Naveen Kumar ◽  
Kam Y. J. Zhang ◽  
Pratiksha Srivastava ◽  
Sandeep Bhatia ◽  

Understanding the origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a highly debatable and unsolved challenge for the scientific communities across the world. A key to dissect the susceptibility profiles of animal species to SARS-CoV-2 is to understand how virus enters into the cells. The interaction of SARS-CoV-2 ligands (RBD on spike protein) with its host cell receptor, angiotensin-converting enzyme 2 (ACE2), is a critical determinant of host range and cross-species transmission. In this study, we developed and implemented a rigorous computational approach for predicting binding affinity between 299 ACE2 orthologs from diverse vertebrate species and the SARS-CoV-2 spike protein. The findings show that the spike protein of SARS-CoV-2 can bind to many vertebrate species carrying evolutionary divergent ACE2, implying a broad host range at the virus entry level, which may contribute to cross-species transmission and further viral evolution. Additionally, the present study facilitated the identification of genetic determinants that may differentiate susceptible from the resistant host species based on the conservation of ACE2- spike protein interacting residues in vertebrate host species known to facilitate SARS-CoV-2 infection; however, these genetic determinants warrant in vivo experimental confirmation. The molecular interactions associated with varied binding affinity of distinct ACE2 isoforms in a specific bat species were identified using protein structure analysis, implying the existence of diversified susceptibility of bat species to SARS-CoV-2. The findings from current study highlight the importance of intensive surveillance programs aimed at identifying susceptible hosts, particularly those with the potential to transmit zoonotic pathogens, in order to prevent future outbreaks.

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262482
Katarzyna Papaj ◽  
Patrycja Spychalska ◽  
Patryk Kapica ◽  
André Fischer ◽  
Jakub Nowak ◽  

Based on previous large-scale in silico screening several factor Xa inhibitors were proposed to potentially inhibit SARS-CoV-2 Mpro. In addition to their known anticoagulants activity this potential inhibition could have an additional therapeutic effect on patients with COVID-19 disease. In this study we examined the binding of the Apixaban, Betrixaban and Rivaroxaban to the SARS-CoV-2 Mpro with the use of the MicroScale Thermophoresis technique. Our results indicate that the experimentally measured binding affinity is weak and the therapeutic effect due to the SARS-CoV-2 Mpro inhibition is rather negligible.

Anna Clara Milesi Galdino ◽  
Lívia Viganor ◽  
Matheus Mendonça Pereira ◽  
Michael Devereux ◽  
Malachy McCann ◽  

AbstractTackling microbial resistance requires continuous efforts for the development of new molecules with novel mechanisms of action and potent antimicrobial activity. Our group has previously identified metal-based compounds, [Ag(1,10-phenanthroline-5,6-dione)2]ClO4 (Ag-phendione) and [Cu(1,10-phenanthroline-5,6-dione)3](ClO4)2.4H2O (Cu-phendione), with efficient antimicrobial action against multidrug-resistant species. Herein, we investigated the ability of Ag-phendione and Cu-phendione to bind with double-stranded DNA using a combination of in silico and in vitro approaches. Molecular docking revealed that both phendione derivatives can interact with the DNA by hydrogen bonding, hydrophobic and electrostatic interactions. Cu-phendione exhibited the highest binding affinity to either major (− 7.9 kcal/mol) or minor (− 7.2 kcal/mol) DNA grooves. In vitro competitive quenching assays involving duplex DNA with Hoechst 33258 or ethidium bromide demonstrated that Ag-phendione and Cu-phendione preferentially bind DNA in the minor grooves. The competitive ethidium bromide displacement technique revealed Cu-phendione has a higher binding affinity to DNA (Kapp = 2.55 × 106 M−1) than Ag-phendione (Kapp = 2.79 × 105 M−1) and phendione (Kapp = 1.33 × 105 M−1). Cu-phendione induced topoisomerase I-mediated DNA relaxation of supercoiled plasmid DNA. Moreover, Cu-phendione was able to induce oxidative DNA injuries with the addition of free radical scavengers inhibiting DNA damage. Ag-phendione and Cu-phendione avidly displaced propidium iodide bound to DNA in permeabilized Pseudomonas aeruginosa cells in a dose-dependent manner as judged by flow cytometry. The treatment of P. aeruginosa with bactericidal concentrations of Cu-phendione (15 µM) induced DNA fragmentation as visualized by either agarose gel or TUNEL assays. Altogether, these results highlight a possible novel DNA-targeted mechanism by which phendione-containing complexes, in part, elicit toxicity toward the multidrug-resistant pathogen P. aeruginosa. Graphical abstract

2022 ◽  
Shan Qi ◽  
Javier Mota ◽  
Siu-Hong Chan ◽  
Johanna Villarreal ◽  
Nan Dai ◽  

Methyltransferase like-3 (METTL3) and METTL14 complex transfers a methyl group from S-adenosyl-L-methionine to N6 amino group of adenosine bases in RNA (m6A) and DNA (m6dA). Emerging evidence highlights a role of METTL3-METTL14 in the chromatin context, especially in processes where DNA and RNA are held in close proximity. However, a mechanistic framework about specificity for substrate RNA/DNA and their interrelationship remain unclear. By systematically studying methylation activity and binding affinity to a number of DNA and RNA oligos with different propensities to form inter- or intra-molecular duplexes or single-stranded molecules in vitro, we uncover an inverse relationship for substrate binding and methylation and show that METTL3-METTL14 preferentially catalyzes the formation of m6dA in single-stranded DNA (ssDNA), despite weaker binding affinity to DNA. In contrast, it binds structured RNAs with high affinity, but methylates the target adenosine in RNA (m6A) much less efficiently than it does in ssDNA. We also show that METTL3-METTL14-mediated methylation of DNA is largely restricted by structured RNA elements prevalent in long noncoding and other cellular RNAs.


Objective: This study was aimed to analyze the inhibitory effect of the drugs used in nanocarrier as well as nanoparticles formulation based drug delivery system selected from PubChem database literature against 3CLpro (3C-like protease) receptor of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) by implementing several in silico analysis techniques. Methods: This paper detailed a molecular docking-based virtual screening of 5240 compounds previously utilized in nanoparticle and nanocarrier drug delivery systems utilizing AutoDock Vina software on 3CL protease to discover potential inhibitors using a molecular docking technique. Results: According to the results of the screening, the top two compounds, PubChem Id 58823276 and PubChem Id 60838 exhibited a high affinity for the 3CL protease binding region. Their binding affinities were-9.6 and-8.5 kJ/mol, indicating that they were tightly bound to the target receptor, respectively. These results outperformed those obtained using the co-crystallized native ligand, which exhibited a binding affinity of-7.4 kJ/mol. PubChem Id 60838, the main hit compound in terms of both binding affinity and ADMET analysis, displayed substantial deformability after MD simulation. As a result of the VS and molecular docking techniques, novel 3CL protease inhibitors from the PubChem database were discovered using the Lipinski rule of five and functional molecular contacts with the target protein, as evidenced by the findings of this work. Conclusion: The findings suggest that the compounds discovered may represent attractive opportunities for the development of COVID-19 3CLpro inhibitors and that they need further evaluation and investigation.

2022 ◽  
Berly Cárdenas-Pillco ◽  
Lizbeth Campos-Olazaval ◽  
Patricia López ◽  
Jorge Alberto Aguilar-Pineda ◽  
Pamela Lily Gamero-Begazo ◽  

Abstract Colorectal cancer (CRC) disease has a high mortality rate and has recently involved human profilin II (Pfn2), an actin-binding protein, as a promoter of its invasiveness and progression. This work evaluated the binding affinity of oleanolic acid saponin over Pfn2 and its structural stability. QM and MM techniques were applied to perform geometrical optimization and calculation of the reactive sites from oleanolic acid, whereas molecular docking and MD simulations for protein-ligand interaction under physiological conditions. Oleanolic acid saponin showed a high binding affinity to the Pfn2 PLPbinding site. Analysis of the protein-ligand structure suggests saponin as a molecule with high potential for developing new drugs against Pfn2 in colorectal cancer cells.

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