Biology subjects

Moin, A. T.

Publications and source records attributed to Moin, A. T..

9 recordsLinked to original sources

bioRxiv2023

Integrated Computational Biophysics approach for Drug Discovery against Nipah Virus

The Nipah virus (NiV) poses a pressing global threat to public health due to its high mortality rate, multiple modes of transmission, and lack of effective treatments. NiV glycoprotein G (NiV-G) emerges as a promising target for NiV drug discovery due to its essential role in viral entry and membrane fusion. Therefore, in this study we applied an integrated computational and biophysics approach to identify potential inhibitors of NiV-G within a curated dataset of Peruvian phytochemicals. Our virtual screening results indicated that these compounds could represent a natural source of potential NiV-G inhibitors with {Delta}G values ranging from -8 to -11 kcal/mol. Among them, Procyanidin B2, B3, B7, and C1 exhibited the highest binding affinities and formed the most molecular interactions with NiV-G. Molecular dynamics simulations revealed the induced-fit mechanism of NiV-G pocket interaction with these procyanidins, primarily driven by its hydrophobic nature. Non-equilibrium free energy calculations were employed to determine binding affinities, highlighting Procyanidin B3 and B2 as the ligands with the most substantial interactions. Overall, this work underscores the potential of Peruvian phytochemicals, particularly procyanidins B2, B3, B7, and C1, as lead compounds for developing anti-NiV drugs through an integrated computational biophysics approach. Key pointsO_LINipah Virus (NiV) Threat: NiV is a severe public health risk due to its high mortality rate, broad host range, multiple transmission modes, and lack of effective treatment. Outbreaks have occurred frequently in South and Southeast Asia, particularly in Bangladesh and India, leading to high fatality rates. C_LIO_LICross-Border Concerns: NiVs ability to transmit between humans and domestic animals raises concerns about its potential to cross regional borders and cause pandemics. It has been recognized as a high-priority pathogen by the World Health Organization. C_LIO_LILack of Treatment: Currently, there are no approved specific antiviral treatments or vaccines for NiV. Patients receive supportive care and some drugs used for other viruses, despite their side effects. C_LIO_LITargeting NiV Glycoprotein G: The study focuses on NiV glycoprotein G (NiV-G) as a target for potential anti-Nipah drugs due to its crucial role in viral entry. This glycoprotein mediates viral attachment and entry into host cells. C_LIO_LIComputational Drug Discovery: The research employs computational methods, including virtual screening and molecular dynamics simulations, to identify potential inhibitors of NiV-G from a dataset of Peruvian phytochemicals, particularly procyanidins B2, B3, B7, and C1. These compounds showed promising binding affinities, stable interactions, and favorable binding energies with NiV-G, making them potential lead compounds for drug development. C_LI

microbiology↗

bioRxiv2023

Development and Characterization of Co-crystals Assisted with In-silico Screening for Solubility and Permeability Enhancement of Curcumin

Despite being a promising phytochemical, Curcumins potential applications are limited due to its classification in BCS class IV, which is associated with low water solubility and permeability. Enhancing the bioavailability of BCS class IV drugs presents a significant challenge, but crystal chemistry provides a hopeful avenue for overcoming this hurdle. In this research, co-crystals of Curcumin were developed to improve both solubility and permeability. Unlike traditional methods that require extensive trial-based lab work and time-consuming screening of co-formers, the use of molecular docking in In-silico co-former screening offers a scientific and rational approach to selecting suitable partners. In this study, two distinct co-crystals were synthesized using a solvent evaporation technique with methanol as the solvent, employing a 1:1 molar ratio. L-proline and piperine were chosen as co-formers to enhance solubility and permeability, respectively. The co-crystals underwent optimization and characterization through Design of Experiments (DOE). Comparing the dissolution study results for the same curcumin concentration, the cumulative drug release (CDR) after 8 hours was 20% for pure curcumin and an impressive 71% for curcumin-L-proline co-crystals. The permeability study, conducted over four hours using the everted gut sac method in phosphate buffer pH 6.8, revealed curcumins permeability to be less than 0.05 mg/mL, while curcumin-piperine co-crystals exhibited a five-fold increase (0.2545 mg/mL) in permeability. The co-crystals formed through a molecular ratio of 1:1 for curcumin-L-proline to enhance solubility and 1:1 for curcumin-piperine to enhance permeability, both demonstrated positive outcomes with support from optimization analysis, FTIR, DSC, SEM, PXRD analysis, and dissolution studies.

pharmacology and toxicology↗

bioRxiv2023

Repurposing Remdesivir for COVID-19: Computational Drug Design Targeting SARS-CoV-2 RNA Polymerase and Main Protease using Molecular Dynamics Approach

The coronavirus disease of 2019 (COVID-19) is a highly contagious respiratory illness that has become a global health crisis with new variants, an unprecedented number of infections, and deaths and demands urgent manufacturing of potent therapeutics. Despite the success of vaccination campaigns around the globe, there is no particular therapeutics approved to date for efficiently treating infected individuals. Repositioning or repurposing previously effective antivirals against RNA viruses to treat COVID-19 patients is a feasible option. Remdesivir is a broad-spectrum antiviral drug that the Food and Drug Administration (FDA) licenses for treating COVID-19 patients who are critically ill patients. Remdesivirs low efficacy, which has been shown in some clinical trials, possible adverse effects, and dose-related toxicities are issues with its use in clinical use. Our study aimed to design potent derivatives of remdesivir through the functional group modification of the parent drug targeting RNA-dependent RNA polymerase (RdRp) and main protease (MPro) of SARS-CoV-2. The efficacy and stability of the proposed derivatives were assessed by molecular docking and extended molecular dynamics simulation analyses. Furthermore, the pharmacokinetic activity was measured to ensure the safety and drug potential of the designed derivatives. The derivatives were non-carcinogenic, chemically reactive, highly interactive, and stable with the target proteins. D-CF3 is one of the designed derivatives that finally showed stronger interaction than the parent drug, according to the docking and dynamics simulation analyses, with both target proteins. However, in vitro and in vivo investigations are guaranteed to validate the findings in the future.

bioinformatics↗

bioRxiv2023

Accelerating Cancer Vaccine Development for Human T-Lymphotropic Virus (HTLV) Using a High-Throughput Molecular Dynamics Approach

Human T-lymphotropic virus (HTLV), a retrovirus belonging to the oncovirus family, has long been linked to be associated with various inflammatory and immunosuppressive disorders. To combat the devastating impact of this virus, our study employed a reverse vaccinology approach to design a multi-epitope-based vaccine targeting the highly virulent subtypes of HTLV. We conducted a comprehensive analysis of the molecular interactions between the vaccine and Toll-like receptors (TLRs), providing valuable insights for future research on preventing and managing HTLV-related diseases and any possible outbreaks. The vaccine was designed by focusing on the envelope glycoprotein gp62, a crucial protein involved in the infectious process and immune mechanisms of HTLV inside the human body. Epitope mapping identified T cell and B cell epitopes with low binding energies, ensuring their immunogenicity and safety. Linkers and adjuvants were incorporated to enhance the vaccines stability, antigenicity, and immunogenicity. Two vaccine constructs were developed, both exhibiting high antigenicity and conferring safety. Vaccine construct 2 demonstrated expected solubility and structural stability after disulfide engineering. Molecular docking analyses revealed strong binding affinity between the vaccine construct 2 and both TLR2 and TLR4. Molecular dynamics simulations indicated that the TLR2-vaccine complex displayed enhanced stability, compactness, and consistent hydrogen bond formation, suggesting a favorable affinity. Contact analysis, Gibbs free energy landscapes, and DCC analysis further supported the stability of the TLR2-vaccine complex, while DSSP analysis confirmed stable secondary structures. MM-PBSA analysis revealed a more favorable binding affinity of the TLR4-vaccine complex, primarily due to lower electrostatic energy. In conclusion, our study successfully designed a multi-epitope-based vaccine targeting HTLV subtypes and provided valuable insights into the molecular interactions between the vaccine and TLRs. These findings should contribute to the development of effective preventive and treatment approaches against HTLV-related diseases.

bioinformatics↗

bioRxiv2023

Unravelling the Oncogenic Potential and Prognostic Significance of CKS1B in Human Lung Adenocarcinoma and Squamous Cell Carcinoma: A Comprehensive Computational Analysis

Lung cancer (LC) confers to radical malignancy with a limited recourse of therapy worldwide. Consequently, LC has become the leading cause of cancer deaths in both men and women globally. Non-small cell lung cancer (NSCLC), one of the major LC types and accountable for a greater share of these cancer-associated deaths, further branches out to adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). A dearth of evident clinical symptoms coupled with the diagnosis feasibility only after advanced metastasis raises the need for precision in treatment apart from the existing chemical drug treatments. Precise guidance can be entailed by targeted therapies, utilizing the potential and thoroughly evaluated differentially expressed genes of cancer under speculation for tumor treatments. Cyclin-dependent kinase regulatory subunit 1B (CKS1B), a member of the conserved cyclin kinase subunit 1 (CKS1) protein family, regulates the cell cycle. Increasing evidence revealed that up-regulation of the CKS1B gene is associated with multiple human-related cancers, indicates its potential use as a targeted therapeutic for early detection and treatment. CKS1B has been found to be associated with poor prognosis in both LUAD and LUSC, while the prognostic significance of CKS1B in other types of cancer is not well established. Herein, we have performed a comprehensive bioinformatics analysis of factors involved in LUAD and LUSC with CKS1B and discussed its role as a potential biomarker for early lung cancer detection and treatment. While these evaluations demonstrate the immunotherapeutic features and prognostic value of CKS1B, further in vivo and in vitro studies are required to determine the accuracy of final applications.

cancer biology↗

bioRxiv2022

A Multi-omics Study on the Oncogenic Roles and Clinical Significance of Dynactin Family Gene (DCTN1-6) Expression in Liver Hepatocellular Carcinoma

In this study, we employed a comprehensive database mining approach to examine the possible oncogenic roles and clinical relevance of Dynactin family genes (DCTN1-6) in Liver Hepatocellular Carcinoma (LIHC). All the DCTNs were observed to be differentially expressed in LIHC tissues compared to the adjacent normal liver tissues. Most of the DCTNs were discovered to be aberrantly methylated (less methylated) and contain multiple somatic mutations (alteration frequency: 0.2-2.5%) in LIHC tissues. Overexpression of DCTNs was mostly associated with poor overall and relapse-free survival of LIHC patients. Alongside, all the DCTN genes were reported to be overexpressed across different demographic and clinical conditions, i.e., age, cancer stage, tumor grades, and metastatic stages of LIHC patients. DCTN expression was also associated with the infiltration levels of different immune cells, i.e., B cell, T cell, and macrophages in LIHC microenvironment. The co-expressed genes of DCTNs in the LIHC tissues were previously found to be involved in oncogenic processes in different cancer types and control crucial biological processes, i.e., nucleotide metabolism, RNA degradation, and chromosome organization. Later, the expression pattern of DCTNs was validated in two independent microarray datasets (i.e., GSE17856, GSE98383), which also supported our initial findings. All these findings suggest that DCTNs and their transcriptional and translational products are potential prognostic and therapeutic targets for LIHC diagnosis and treatment. This study will help further the development of DCTN-based diagnostic and therapeutic measures for LIHC and translate them into clinical implications.

genomics↗

bioRxiv2022

Identifying Proteasome 26S Subunit, ATPase (PSMC) Family Genes as the Prognostic Indicators and Therapeutic Targets in Lung Adenocarcinoma

This study explored the prognostic and therapeutic potentials of multiple Proteasome 26S Subunit, ATPase (PSMC) family of genes (PSMC1-5) in lung adenocarcinoma (LUAD) diagnosis and treatment. All the PSMCs were found to be differentially expressed (upregulated) at the mRNA and protein levels in LUAD tissues. The promoter and multiple coding regions of PSMCs were reported to be differentially and distinctly methylated, which may serve in the methylation-sensitive diagnosis of LUAD patients. Multiple somatic mutations (alteration frequency: 0.6-2%) were observed along the PSMCs coding regions in LUAD tissues that could assist in the high-throughput screening of LUAD patients. A significant association between PSMCs overexpression and LUAD patients poor overall and relapse-free survival (p<0.05, HR:>1.3) and individual cancer stages (p<0.001) was discovered, which justifies PSMCs as the ideal targets for LUAD diagnosis. Multiple immune cells and modulators (i.e., CD274, IDO1) were found to be associated with PSMCs expression in LUAD tissues that could aid in formulating PSMC-based diagnostic measures and therapeutic interventions for LUAD. Functional enrichment analysis of neighbor genes of PSMCs in LUAD tissues revealed different genes (i.e., SLIRP, PSMA2, NUDSF3) previously known to be involved in oncogenic processes and metastasis co-expressed with PSMCs, which could also be investigated further. Overall, this study recommends that PSMCs and their transcriptional and translational products are potential candidates for LUAD diagnostic and therapeutic measure discovery. However, further laboratory research is needed to validate the findings of this experiment.

cancer biology↗

bioRxiv2022

Expression Analysis, Molecular Characterization and Prognostic Evaluation on TMED4 and TMED9 Gene Expression in Glioma

Here, we utilized a database mining approach to unfold the prognostic and therapeutic potentials of Transmembrane EmP24 Trafficking Protein 4 (TMED4) and 9 (TMED) coding gene expressions in glioma. Both the genes were found to be overexpressed at the mRNA and protein level in low grade glioma (LGG) and glioblastoma multiforme (GBM) tissues including different glioma cell lines. Significant increase in the expression level of these genes with advancing glioma patients age, glioma grades and histological subtypes was observed. Differential and distinct promoter and coding sequence methylation pattern of TMED4 and TMED9 was observed in LGG and GBM tissues that may aid in methylation-sensitive diagnosis of glioma patients. The presence of multiple heterozygous genetic alterations (frequency: 0.4-1.1%) in those genes unveiled their potentials in high-throughput screening of glioma patients. The overexpression of TMED4 and TMED9 genes was associated with poor overall survival (OS) of LGG and GBM patients (HR:>1.6). Association of the expression levels of these genes with different immune cell infiltration levels i.e., B cell and T cell and modulators like CD274 and IL10RB was observed providing assurance in TMED-based diagnostic measure and therapeutic intervention discovery. Furthermore, functional enrichment analysis of the neighbor genes of TMED4 and TMED9 revealed that they are involved in metal ion binding, focal adhesion of cells and protein processing, and the deregulation of these activities are associated with gliomagenesis. Altogether, this study suggests that TMED4 and TMED9 are potential prognostic and therapeutic targets for glioma. However, further laboratory research is warranted.

cancer biology↗

bioRxiv2022

Exploring different virulent proteins of human respiratory syncytial virus for designing a novel epitope-based polyvalent vaccine: Immunoinformatics and molecular dynamics approaches

Human Respiratory Syncytial Virus (RSV) is one of the most prominent causes of lower respiratory tract infections (LRTI), contributory to infecting people from all age groups - a majority of which comprises infants and children. The implicated severe RSV infections lead to numerous deaths of multitudes of the overall population, predominantly the children, every year. Consequently, despite several distinctive efforts to develop a vaccine against the RSV as a potential countermeasure, there is no approved or licensed vaccine available yet, to control the RSV infection effectively. Therefore, through the utilization of immunoinformatics tools, a computational approach was taken in this study, to design and construct a multi-epitope polyvalent vaccine against the RSV-A and RSV-B strains of the virus. Potential predictions of the T-cell and B-cell epitopes were followed by extensive tests of antigenicity, allergenicity, toxicity, conservancy, homology to human proteome, transmembrane topology, and cytokine-inducing ability. The most promising epitopes (i.e. 13 CTL epitopes, 9 HTL epitopes, and 10 LBL epitopes) exhibiting full conservancy were then selected for designing the peptide fusion with appropriate linkers, having hBD-3 as the adjuvant. The peptide vaccine was modeled, refined, and validated to further improve the structural attributes. Following this, molecular docking analysis with specific TLRs was carried out which revealed excellent interactions and global binding energies. Additionally, molecular dynamics (MD) simulation was conducted which ensured the stability of the interactions between vaccine and TLR. Furthermore, mechanistic approaches to imitate and predict the potential immune response generated by the administration of vaccines were determined through immune simulations. Owing to an overall evaluation, in silico cloning was carried out in efforts to generate recombinant pETite plasmid vectors for subsequent mass production of the vaccine peptide, incorporated within E.coli. However, more in vitro and in vivo experiments can further validate its efficacy against RSV infections.

immunology↗