PROTEIN-NUCLEIC ACID INTERFACE (PNAI) INHIBITOR DRUG MOLECULES FOR SARS-COV-2

10.26434/chemrxiv.12026736 ◽

2020 ◽

Author(s):

Hamdullah Khadim Sheikh ◽

Tanzila Arshad ◽

Zainab Sher Mohammad ◽

Iqra Arshad ◽

Mohtasheemul Hassan

Keyword(s):

Nucleic Acid ◽

Binding Energy ◽

Protease Inhibitors ◽

Atomic Structure ◽

Molecular Structures ◽

Drug Molecules ◽

Protein Nucleic Acid ◽

Inhibitor Drug

<p>In this research we used the structure of SARS-CoV-2 related, recently mapped, atomic structure of nsp10/16 proteins for docking with some known drug molecular structures at pH 7 and 5. Chosen molecules were azo -N=N- and -COOH derivatives. It was revealed that the molecules showed good binding energy with nsp10/16 protein at both pH. These molecules can act as protein-nucleic acid interface (PNAI) inhibitor drug molecules. Such molecules can be used in combination with polymerase and protease inhibitors for treatment of SARS-CoV-2. </p>

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Evaluation on the performance of MM/PBSA in nucleic acid-protein systems

Chinese Physics B ◽

10.1088/1674-1056/ac3a5c ◽

2021 ◽

Author(s):

Yuan-Qiang Chen ◽

Yan-Jing Sheng ◽

Hong-Ming Ding ◽

Yu-Qiang Ma

Keyword(s):

Nucleic Acid ◽

Binding Energy ◽

Molecular Mechanics ◽

Pearson Correlation ◽

Electrostatic Energy ◽

Pearson Correlation Coefficient ◽

Acid Protein ◽

Poisson Boltzmann ◽

Protein Nucleic Acid ◽

Better Than

Abstract The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method has been widely used in predicting the binding affinity among the ligands, the proteins and the nucleic acids. However, the accuracy of the predicted binding energy by the standard MM/PBSA is not always good, especially in highly charged systems. In this work, we take the protein-nucleic acid complexes as an example, and showed that the use of screening electrostatic energy (instead of coulomb electrostatic energy) in molecular mechanics can greatly improve the performance of MM/PBSA. In particular, the Pearson correlation coefficient of dataset II in the modified MM/PBSA (i.e., screening MM/PBSA) is about 0.52, much better than that (<0.33) in the standard MM/PBSA. Further, we also evaluate the effect of the solute dielectric constant and the salt concentration on the performance of the screening MM/PBSA. The present study highlights the potential power of the screening MM/PBSA for predicting the binding energy in highly charged bio-systems.

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Snapshot blotting: The transfer of nucleic acids and nucleoprotein complexes from electrophoresis gels to EM grids

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100124215 ◽

1992 ◽

Vol 50 (1) ◽

pp. 762-763

Author(s):

Stephen D. Jett

Keyword(s):

Nucleic Acid ◽

Nucleic Acids ◽

Nucleic Acid Binding ◽

Mobility Shift ◽

Carbon Coated ◽

Nucleoprotein Complexes ◽

Mobility Shift Assay ◽

Protein Nucleic Acid ◽

Gel Mobility Shift ◽

Nucleic Acid Interactions

The electrophoresis gel mobility shift assay is a popular method for the study of protein-nucleic acid interactions. The binding of proteins to DNA is characterized by a reduction in the electrophoretic mobility of the nucleic acid. Binding affinity, stoichiometry, and kinetics can be obtained from such assays; however, it is often desirable to image the various species in the gel bands using TEM. Present methods for isolation of nucleoproteins from gel bands are inefficient and often destroy the native structure of the complexes. We have developed a technique, called “snapshot blotting,” by which nucleic acids and nucleoprotein complexes in electrophoresis gels can be electrophoretically transferred directly onto carbon-coated grids for TEM imaging.

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Lead Molecule Prediction and Characterization for Designing MERS-CoV 3C-like Protease Inhibitors: An In silico Approach

Current Computer - Aided Drug Design ◽

10.2174/1573409914666180629151906 ◽

2018 ◽

Vol 15 (1) ◽

pp. 82-88 ◽

Cited By ~ 1

Author(s):

Md. Mostafijur Rahman ◽

Md. Bayejid Hosen ◽

M. Zakir Hossain Howlader ◽

Yearul Kabir

Keyword(s):

Binding Energy ◽

Middle East ◽

Virtual Screening ◽

In Silico ◽

Screening Method ◽

Middle East Respiratory Syndrome ◽

Cytochrome P450 Enzymes ◽

Drug Molecules ◽

Essential Enzyme ◽

Reduced Toxicity

Background: 3C-like protease also called the main protease is an essential enzyme for the completion of the life cycle of Middle East Respiratory Syndrome Coronavirus. In our study we predicted compounds which are capable of inhibiting 3C-like protease, and thus inhibit the lifecycle of Middle East Respiratory Syndrome Coronavirus using in silico methods. </P><P> Methods: Lead like compounds and drug molecules which are capable of inhibiting 3C-like protease was identified by structure-based virtual screening and ligand-based virtual screening method. Further, the compounds were validated through absorption, distribution, metabolism and excretion filtering. Results: Based on binding energy, ADME properties, and toxicology analysis, we finally selected 3 compounds from structure-based virtual screening (ZINC ID: 75121653, 41131653, and 67266079) having binding energy -7.12, -7.1 and -7.08 Kcal/mol, respectively and 5 compounds from ligandbased virtual screening (ZINC ID: 05576502, 47654332, 04829153, 86434515 and 25626324) having binding energy -49.8, -54.9, -65.6, -61.1 and -66.7 Kcal/mol respectively. All these compounds have good ADME profile and reduced toxicity. Among eight compounds, one is soluble in water and remaining 7 compounds are highly soluble in water. All compounds have bioavailability 0.55 on the scale of 0 to 1. Among the 5 compounds from structure-based virtual screening, 2 compounds showed leadlikeness. All the compounds showed no inhibition of cytochrome P450 enzymes, no blood-brain barrier permeability and no toxic structure in medicinal chemistry profile. All the compounds are not a substrate of P-glycoprotein. Our predicted compounds may be capable of inhibiting 3C-like protease but need some further validation in wet lab.

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Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins

International Journal of Molecular Sciences ◽

10.3390/ijms22052647 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2647

Author(s):

M. Quadir Siddiqui ◽

Maulik D. Badmalia ◽

Trushar R. Patel

Keyword(s):

Nucleic Acid ◽

Nuclear Export ◽

Consensus Sequence ◽

Nuclear Export Signal ◽

Bioinformatic Analysis ◽

Nucleic Acid Binding ◽

Protein Protein Interaction ◽

Lim Domains ◽

Protein Nucleic Acid ◽

And Function

Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and functions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share similarities with transcriptional regulators and have positively charged electrostatic patches, which may indicate that they have previously unanticipated nucleic acid binding properties. Intrinsic dynamics analysis of Lim domains suggest that only Lim1 has similar internal dynamics properties, unlike Lim2/3. Furthermore, we analyzed protein expression and mutational frequency in various malignancies, as well as mapped protein-protein interaction networks they are involved in. Overall, our comprehensive bioinformatic analysis suggests that these proteins may play important roles in mediating protein-protein and protein-nucleic acid interactions.

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Purification and functional characterization of adenovirus ts111A DNA-binding protein. Fluorescence studies of protein-nucleic acid binding.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(19)39444-x ◽

1990 ◽

Vol 265 (10) ◽

pp. 5875-5882

Author(s):

M L Meyers ◽

K M Keating ◽

W J Roberts ◽

K R Williams ◽

J W Chase ◽

...

Keyword(s):

Nucleic Acid ◽

Dna Binding ◽

Binding Protein ◽

Functional Characterization ◽

Dna Binding Protein ◽

Nucleic Acid Binding ◽

Protein Fluorescence ◽

Fluorescence Studies ◽

Protein Nucleic Acid

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Computer-aided identification of a series of novel ligands showing high potency as hepatitis C virus NS3/4A protease inhibitors

Bulletin of the National Research Centre ◽

10.1186/s42269-020-00467-w ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Stephen Ejeh ◽

Adamu Uzairu ◽

Gideon Adamu Shallangwa ◽

Stephen E. Abechi

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Binding Energy ◽

Protease Inhibitor ◽

Protease Inhibitors ◽

Antiviral Agents ◽

High Potency ◽

Direct Acting Antiviral ◽

Direct Acting ◽

Direct Acting Antiviral Agents

Abstract Background Hepatitis C virus (HCV) is a global medical condition that causes several life-threatening chronic diseases in the liver. The conventional interferon-free treatment regimens are currently in use by a blend of direct-acting antiviral agents (DAAs) aiming at the viral NS3 protease. However, major concerns may be the issue of DAA-resistant HCV strains and the limited availability to the DAAs due to their high price. Due to this crisis, the developments of a new molecule with high potency as an NS3/4A protease inhibitor of the hepatitis-C virus remain a high priority for medical research. This study aimed to use in-silico methods to identify high potent molecule as an NS3/4A protease inhibitor and investigating the binding energy of the identified molecule in comparison with approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) through molecular docking. Results The model obtained by in-silico method have the following statistical records, coefficient of determination (r2) of 0.7704, cross-validation (q2LOO = 0.6914); external test set (r2(pred) = 0.7049) and Y-randomization assessment (cR2p = 0.7025). The results from the model were used to identify 12 new potential human HCV NS3/4A protease inhibitors, and it was observed that the identified molecule is well-fixed when docked with the receptor and was found to have the lowest binding energy of − 10.7, compared to approved direct-acting antiviral agents (Telaprevir, Simeprevir, and Voxilaprevir) with − 9.5, − 10.0, − 10.5 binding energy, respectively. Conclusion The binding affinity (− 10.7) of the newly identified molecule docked with 3D structures of HCV NS3/4a protease/helicase (PDB ID: 4A92) was found to be better than that of Telaprevir, Simeprevir, and Voxilaprevir (approved direct-acting antiviral agents) which are − 9.5, − 10.0, and − 10.5, respectively. Hence, a novel molecule was identified showing high potency as HCV NS3/4a protease inhibitors.

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