Binding Affinity
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2021 ◽  
Vol 12 (1) ◽  
pp. 186-214
Manish Devgun ◽  
Sushil Prasad ◽  
SukhbirLal Khokra ◽  
Rakesh Narang

Molecular docking is the identification of ligand’s correct binding geometry i.e pose in the binding site and estimation of its binding affinity for the rational design of drug molecule. The current study endeavored the high throughput insilico screening of 24 compounds docked with their respective protein using PyRx-Virtual Screening Tool software. Out of 24 compounds, almost all test compounds showed a very good binding affinity score. Fluconazole was used as a standard drug in case of Antifungal, Ciprofloxacin in case of Antibacterial, and Albendazole in case of Antihelmintics. More negative is the binding free energy score, more favorable is the pose for binding to protein active site. Based on H-bond interactions of these 24 compounds, Compounds 3a5, 3c3, 3d5, 3d6 were found to be the similar outcome for antifungal activity as fluconazole, Compound3a1 for antibacterial, and Compounds 3b5, 3d6 for the antihelmintic agent. Furthermore, the affinity of any small ligand molecules can be considered as an extraordinary tool in the field of drug design and offer imminent in future examination to build up potent antimicrobial agents.

2021 ◽  
Vol 8 ◽  
Aweke Mulu Belachew ◽  
Asheber Feyisa ◽  
Seid Belay Mohamed ◽  
Jerusalem Fekadu W/Mariam

Due to the rapid growth of the COVID-19 pandemic and its outcomes, developing a remedy to fight the predicament is critical. So far, it has infected more than 214,468,601 million people and caused the death of 4,470,969 million people according to the August 27, 2021, World Health Organization's (WHO) report. Several studies have been published on both computational and wet-lab approaches to develop antivirals for COVID-19, although there has been no success yet. However, the wet-lab approach is laborious, expensive, and time-consuming, and computational techniques have screened the activity of bioactive compounds from different sources with less effort and cost. For this investigation, we screened the binding affinity of fungi-derived bioactive molecules toward the SARS coronavirus papain-like protease (PLpro) by using computational approaches. Studies showed that protease inhibitors can be very effective in controlling virus-induced infections. Additionally, fungi represent a vast source of bioactive molecules, which could be potentially used for antiviral therapy. Fifty fungi-derived bioactive compounds were investigated concerning SARS-CoV-2 PLpro by using Auto Dock 4.2.1, Gromacs 2018. 2, ADMET, Swiss-ADME, FAF-Drugs 4.023, pKCSM, and UCLA-DOE server. From the list of the screened bioactive compounds, Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin were selected with the Auto-Dock results of −8.68, −7.52, −10.46, and −10.58 Kcal/mol, respectively, based on their binding affinity compared to the reference drug. We presented the drug likeliness, toxicity, carcinogenicity, and mutagenicity of all compounds using ADMET analysis. They interacted with the amino acid residues, Gly163, Trp106, Ser111, Asp164, and Cys270, through hydrogen bonds. The root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg) values revealed a stable interaction. From the overall analyses, we can conclude that Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin are classified as promising candidates for PLpro, thus potentially useful in developing a medicine for COVID-19.

2021 ◽  
Min-Cheol Lim ◽  
Eun Seob Lim ◽  
Jeong-A Lim ◽  
Sung-Wook Choi ◽  
Hyun-Joo Chang

Abstract BackgroundAptamer-based methods for detecting pesticides are more efficient than antibody-based methods as aptamers have high thermal stability, low molecular weight, easy modification, and low cost. However, only few studies on SELEX performed in combination with next generation sequencing (NGS) to screen aptamers specific for pesticides have been reported. Therefore, this study aimed to develop the systematic evolution of ligands by exponential enrichment (SELEX) process, combined with NGS, to select aptamers specific to the pesticide, diazinon, which was fixed on a sol-gel-coated nanoporous anodized aluminum oxide membrane. Methods and resultsThe frequency of specific nucleotide sequences obtained after SELEX rounds was analyzed using NGS. Nine sequences with the highest frequency after SELEX round 10 followed by NGS were selected and tested to derive their binding affinity with the target, diazinon, through circular dichroism (CD) spectrophotometry. The CD signal difference of the aptamer candidates ranged from 0.13 to 2.242 mdeg between diazinon-only treated and diazinon-aptamer-treated samples at a wavelength near 270 nm. Aptamer D-4, which had the highest binding affinity from CD spectrophotometry analysis, showed no cross-reactivity with non-target pesticides, such as baycarb, bifenthrin, and pyridaben, but interacted with the other pesticides, fipronil and 2-phenylphenol.ConclusionsThe proposed SELEX process combined with NGS for the discovery of aptamers for new targets can shorten the SELEX cycle by reducing the number of SELEX rounds to 10 or less. Therefore, an efficiently selected aptamer is highly expected to be used for the detection of pesticides in foods in the field.

2021 ◽  
Vol 12 (1) ◽  
Pengcheng Han ◽  
Chao Su ◽  
Yanfang Zhang ◽  
Chongzhi Bai ◽  
Anqi Zheng ◽  

AbstractMultiple SARS-CoV-2 variants of concern (VOCs) have been emerging and some have been linked to an increase in case numbers globally. However, there is yet a lack of understanding of the molecular basis for the interactions between the human ACE2 (hACE2) receptor and these VOCs. Here we examined several VOCs including Alpha, Beta, and Gamma, and demonstrate that five variants receptor-binding domain (RBD) increased binding affinity for hACE2, and four variants pseudoviruses increased entry into susceptible cells. Crystal structures of hACE2-RBD complexes help identify the key residues facilitating changes in hACE2 binding affinity. Additionally, soluble hACE2 protein efficiently prevent most of the variants pseudoviruses. Our findings provide important molecular information and may help the development of novel therapeutic and prophylactic agents targeting these emerging mutants.

2021 ◽  
Rong Yang ◽  
Kan Wang ◽  
Tuo Li ◽  
Mianmian Liao ◽  
Mingwang Kong

Abstract Background: Alzheimer's disease (AD) is the commonest neurodegenerative disease characterized with a progressive loss of cognitive functions and memory decline. Kai Xin San (KXS), a traditional Chinese herbal classic prescription, has been used to ameliorate cognitive dysfunction for thousands of years. However, its specific pharmacological molecular mechanisms have not been fully clarified.Methods: The ingredients of KXS and their corresponding targets were firstly screened from ETCM database. AD-related target proteins were obtained from Malacards database and DisGeNet database. Venn diagram was used to intersect the common targets between KXS and AD. Then, key ingredients and key targets were identified from compound-target-disease network and protein-protein interaction (PPI) network analysis respectively. Moreover, the binding affinity between the key ingredients and targets were verified by molecular docking. KEGG enrichment analysis further predicted the potential key signaling pathway involved in the treatment of KXS on AD, and the predicted signaling pathway was validated via experimental approach.Results: A total of 38 ingredients and 469 corresponding targets were screened, and 264 target proteins associated with AD were obtained. Compound-target-disease network and PPI identified the key active ingredients and targets, which correlate with the treatment of KXS on AD. Molecular docking revealed a good binding affinity between key ingredients and targets. KEGG pathway analysis suggested the potential effect of KXS in treatment of AD via Aβ-GSK3β-Tau pathway. Aβ1-42-injected induced a decline in spatial learning and memory and upregulated the expression of GSK3β and CDK5 along with the downregulated PP1 and PP2 expression. However, KXS significantly improve the cognitive deficits induced by Aβ1-42, decrease the GSK3β and CDK5 levels and increase the expression of PP1 and PP2.Conclusions: Our research elucidated that KXS exerted neuroprotective effects through regulating the Aβ-GSK3β-Tau signaling pathway, which provided a novel insight into the therapeutic mechanism of KXS in treatment of AD.

Drug Research ◽  
2021 ◽  
Sureshbabu Ram Kumar Pandian ◽  
Selvaraj Kunjiappan ◽  
Parasuraman Pavadai ◽  
Velmurugan Sundarapandian ◽  
Vivek Chandramohan ◽  

AbstractUrsolic acid (UA), a pentacyclic triterpenoid and a phytochemical, is a potent inhibitory agent against proliferation of various tumors. Polyhydroxybutyrate nanoparticles (PHB NPs) are preferred in therapeutics due to their drug-stabilizing property and enhanced biological activity. In this study, PHB NPs were utilized to deliver and enhance the bioavailability of UA against cancer cells (HeLa). Further, molecular docking and dynamic studies were conducted to calculate the binding affinity and stability of UA at the active site of target protein (epidermal growth factor receptor-EGFR). The PHB NPs revealed the average size as 150–200 nm in TEM, which were used in subsequent experiments. The cytoplasmic uptake of nanoparticles was confirmed by florescent microscopy. The encapsulation potential of PHB NPs with UA was assessed by UV–visible spectrophotometer as 54%. Besides, the drug release behavior, cytotoxicity and the regulation of apoptosis were investigated in vitro. The cytotoxicity results revealed that the maximum efficiency of drug delivery was at 96th hour.

2021 ◽  
Vol 29 (4) ◽  
Radhiahtul Raehan Mustafa ◽  
Rashidah Sukor ◽  
Siti Mariam Mohd Nor ◽  
Nazamid Saari ◽  
Farina Mustaffa Kamal ◽  

Antibodies are glycoproteins found in peritoneal fluid, serum, and blood. The antibody-based assay has been used for broad applications such as immunodiagnostic and other biomedical applications. Depending on the intended application, a highly purified polyclonal antibody could be used as an alternative. Purification of antibodies from anti-sera has been proven as one of the methods to enhance the binding affinity of antibodies towards its antigen. We report herein the enhancement of the binding affinity of anti-hapten polyclonal IgG recognizing mitragynine using affinity purification. Serum from the terminal bleed of New Zealand White (NZW) rabbits immunized with mitragynine conjugated with cationized– bovine serum albumin at methyl ester (C22-MG-cBSA), or aromatic ether modification (C9-MG-cBSA) were subjected to HiTrap Protein G affinity purification using fast protein liquid chromatography (FPLC). The elution peak from chromatography fractions was analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. Here, we report the binding of polyclonal antibodies produced from inoculation of either C22-MG-cBSA or C9-MG-cBSA immunogens of which mitragynine-ovalbumin (MG-OVA) was used as coating antigen in the ELISA assay. Non purified anti-sera from C22-MG-cBSA-inoculated rabbits showed higher titer than C9-MG-cBSA at 1/128 000 and 1/32 000 dilutions, respectively. The affinity of purified poly-IgGs from rabbits immunized with C22-MG-cBSA showed a mean Kd value of 7.965 × 10-6 μM, which was lower than those immunized with C9-MG-cBSA at mean Kd of 1.390 × 10-4 μM. In addition, the purified poly- IgGs showed higher binding towards MG-OVA than non-purified anti-sera at comparable protein concentrations. These results indicated that the higher binding affinity of purified polyclonal IgG is due to the reduced competition among polyclonal antibodies with non- IgG proteins that co-existed in the non-purified anti-sera after the affinity purification.

2021 ◽  
Vol 4 (1) ◽  
Ko-Han Lee ◽  
Yu-Chuan Chang ◽  
Ting-Fu Chen ◽  
Hsueh-Fen Juan ◽  
Huai-Kuang Tsai ◽  

AbstractThe selection of peptides presented by MHC molecules is crucial for antigen discovery. Previously, several predictors have shown impressive performance on binding affinity. However, the decisive MHC residues and their relation to the selection of binding peptides are still unrevealed. Here, we connected HLA alleles with binding motifs via our deep learning-based framework, MHCfovea. MHCfovea expanded the knowledge of MHC-I-binding motifs from 150 to 13,008 alleles. After clustering N-terminal and C-terminal sub-motifs on both observed and unobserved alleles, MHCfovea calculated the hyper-motifs and the corresponding allele signatures on the important positions to disclose the relation between binding motifs and MHC-I sequences. MHCfovea delivered 32 pairs of hyper-motifs and allele signatures (HLA-A: 13, HLA-B: 12, and HLA-C: 7). The paired hyper-motifs and allele signatures disclosed the critical polymorphic residues that determine the binding preference, which are believed to be valuable for antigen discovery and vaccine design when allele specificity is concerned.

2021 ◽  
Vol 11 (1) ◽  
Emina Ikeuchi ◽  
Daisuke Kuroda ◽  
Makoto Nakakido ◽  
Akikazu Murakami ◽  
Kouhei Tsumoto

AbstractThe high binding affinities and specificities of antibodies have led to their use as drugs and biosensors. Single-domain VHH antibodies exhibit high specificity and affinity but have higher stability and solubility than conventional antibodies as they are single-domain proteins. In this work, based on physicochemical measurements and molecular dynamics (MD) simulations, we have gained insight that will facilitate rational design of single-chain VHH antibodies. We first assessed two homologous VHH antibodies by differential scanning calorimetry (DSC); one had a high (64.8 °C) and the other a low (58.6 °C) melting temperature. We then generated a series of the variants of the low stability antibody and analyzed their thermal stabilities by DSC and characterized their structures through MD simulations. We found that a single mutation that resulted in 8.2 °C improvement in melting temperature resulted in binding affinity an order of magnitude lower than the parent antibody, likely due to a shift of conformational space explored by the single-chain VHH antibody. These results suggest that the delicate balance among conformational stability, binding capability, and conformational space explored by antibodies must be considered in design of fully functional single-chain VHH antibodies.

Galla Rajitha ◽  
Murthi Vidya Rani ◽  
Umakanth Naik Vankadoth ◽  
Amineni Umamaheswari

Aims: The genomic and non-genomic actions of human estrogen receptor α (hERα) play a crucial role in breast epithelial cell proliferation and survival, as well as mammary tumorigenesis. hERα has been proved as a potential target for breast cancer therapy over the last 3 decades. Hence designing novel inhibitors targeting hERα can be a valuable approach in breast cancer therapy. Study Design:  In the present study, the goal is to identify novel hERα inhibitors through molecular docking, AI based virtual screening and interaction fingerprint analysis. Place and Duration of Study: Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India in between July 2021-sep 2021. Methodology: Molecular docking studies were performed using the human estrogen receptor alpha ligand-binding domain in complex with 4-hydroxytamoxifen (PDB: 3ERT) against existing compounds from literature. The best docked existing compound and co-crystal ligand were subjected to shape screening against 28 million compounds and resulted compounds constituted the hERα inhibitor dataset which was subjected to rigid receptor docking. Further, interaction fingerprint analysis was applied as complimentary method to docking for comparing the similarity of predicted binding poses of proposed leads with that of reference binding pose. Results: Co-crystal ligand (4-OHT) and E99 exhibited better binding affinity among existing ligand set. Rigid receptor docking studies resulted in four lead compounds possessing better docking scores than 4-OHT and E99. Moreover, leads showed favorable absorption, distribution, metabolism, excretion and toxicity properties within the range of 95% FDA approved drugs. Proposed leads showed interactions with binding site residues of hERα similar to that of 4-OHT with better binding affinity. The ability of obtained leads to retrieve actives was validated using receiver operative characteristic (ROC) curve. Conclusion: From above results, it has been observed that the proposed leads have potential to act as novel hERα inhibitors.

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