Investigating the role of hypothetical protein (AAB33144.1) in HIV-1 virus pathogenicity: A comparative study with FDA-Approved inhibitor compounds through In silico analysis and molecular docking.

Aim and objective: Due to the a lot of unexplored proteins in HIV-1, this research aimed to explore the functional roles of a hypothetical protein (AAB33144.1) that might play a key role in HIV-1 pathogenicity. Methods: The homologous protein was identified along with building and validating the 3D structure by searching several bioinformatics tools. Results: Retroviral aspartyl protease and retropepsin like functional domains and motifs, folding pattern (cupredoxins), and subcellular localization in cytoplasmic membrane were determined as biological activity. Besides, the functional annotation revealed that the chosen hypothetical protein possessed protease-like activity. To validate our generated protein 3D structure, molecular docking was performed with five compounds where nelfinavir showed (-8.2 kcal/mol) best binding affinity against HXB2 viral protease (PDB ID: 7SJX) and main protease (PDB ID: 4EYR) protein. Conclusions: This study suggests that the annotated hypothetical protein related to protease action, which may be useful in viral genetics and drug discovery.

Gene silencing of Helicobacter pylori through newly designed siRNA convenes the treatment of gastric cancer.

BACKGROUND: Helicobacter pylori is a gastric pathogen that is responsible for causing chronic inflammation and increasing the risk of gastric cancer development. It is capable of persisting for decades in the harsh gastric environment because of the inability of the host to eradicate the infection. Several treatment strategies have been developed against this bacterium using different antibiotics. But the effectiveness of treating H. pylori has significantly decreased due to widespread antibiotic resistance, including an increased risk of gastric cancer. The small interfering RNAs (siRNA), which is capable of sequence-specific gene-silencing can be used as a new therapeutic approach for the treatment of a variety of such malignancies. In the current study, we rationally designed two siRNA molecules to silence the cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) genes of H. pylori for their significant involvement in developing cancer. METHODS: We selected a common region of all the available transcripts from different countries of CagA and VacA to design the siRNA molecules. The final siRNA candidate was selected based on the results from machine learning algorithms, off-target similarity, and various thermodynamic properties. RESULT: Further, we utilized molecular docking and all atom molecular dynamics (MD) simulations to assess the binding interactions of the designed siRNAs with the major components of the RNA-induced silencing complex (RISC) and results revealed the ability of the designed siRNAs to interact with the proteins of RISC complex in comparable to those of the experimentally reported siRNAs. CONCLUSION: These designed siRNAs should effectively silence the CagA and VacA genes of H. pylori during siRNA mediated treatment in gastric cancer.

Mpropred: A machine learning (ML) driven Web-App for bioactivity prediction of SARS-CoV-2 main protease (Mpro) antagonists.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic emerged in 2019 and still requiring treatments with fast clinical translatability. Frequent occurrence of mutations in spike glycoprotein of SARS-CoV-2 led the consideration of an alternative therapeutic target to combat the ongoing pandemic. The main protease (Mpro) is such an attractive drug target due to its importance in maturating several polyproteins during the replication process. In the present study, we used a classification structure-activity relationship (CSAR) model to find substructures that leads to to anti-Mpro activities among 758 non-redundant compounds. A set of 12 fingerprints were used to describe Mpro inhibitors, and the random forest approach was used to build prediction models from 100 distinct data splits. The data set's modelability (MODI index) was found to be robust, with a value of 0.79 above the 0.65 threshold. The accuracy (89%), sensitivity (89%), specificity (73%), and Matthews correlation coefficient (79%) used to calculate the prediction performance, was also found to be statistically robust. An extensive analysis of the top significant descriptors unveiled the significance of methyl side chains, aromatic ring and halogen groups for Mpro inhibition. Finally, the predictive model is made publicly accessible as a web-app named Mpropred in order to allow users to predict the bioactivity of compounds against SARS-CoV-2 Mpro. Later, CMNPD, a marine compound database was screened by our app to predict bioactivity of all the compounds and results revealed significant correlation with their binding affinity to Mpro. Molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) analysis showed improved properties of the complexes. Thus, the knowledge and web-app shown herein can be used to develop more effective and specific inhibitors against the SARS-CoV-2 Mpro. The web-app can be accessed from https://share.streamlit.io/nadimfrds/mpropred/Mpropred_app.py.

Pathogen-driven gene expression patterns lead to a novel approach to the identification of common therapeutic targets.

Developing a common medication strategy for disease control and management could be greatly beneficial. Investigating the differences between diseased and healthy states using differentially expressed genes aids in understanding disease pathophysiology and enables the exploration of protein-drug interactions. This study aimed to find the most common genes in diarrhea-causing bacteria such as Salmonella enterica serovar Typhimurium, Campylobacter jejuni, Escherichia coli, Shigella dysenteriae (CESS) to find new drugs. Thus, differential gene expression datasets of CESS were screened through computational algorithms and programming. Subsequently, hub and common genes were prioritized from the analysis of extensive protein-protein interactions. Binding predictions were performed to identify the common potential therapeutic targets of CESS. We identified a total of 827 dysregulated genes that are highly linked to CESS. Notably, no common gene interaction was found among all CESS bacteria, but we identified 3 common genes in both Salmonella-Escherichia and Escherichia-Campylobacter infections. Later, out of 73 protein complexes, molecular simulations confirmed 5 therapeutic candidates from the CESS. We have developed a new pipeline for identifying therapeutic targets for a common medication strategy against CESS. However, further wet-lab validation is needed to confirm their effectiveness.

Colorectal Cancer: A Review of Carcinogenesis, Global Epidemiology, Current Challenges, Risk Factors, Preventive and Treatment Strategies.

Colorectal cancer (CRC) is the second most deadly cancer. Global incidence and mortality are likely to be increased in the coming decades. Although the deaths associated with CRC are very high in high-income countries, the incidence and fatalities related to CRC are growing in developing countries too. CRC detected early is entirely curable by surgery and subsequent medications. However, the recurrence rate is high, and cancer drug resistance increases the treatment failure rate. Access to early diagnosis and treatment of CRC for survival is somewhat possible in developed countries. However, these facilities are rarely available in developing countries. Highlighting the current status of CRC, its development, risk factors, and management is crucial in creating public awareness. Therefore, in this review, we have comprehensively discussed the current global epidemiology, drug resistance, challenges, risk factors, and preventive and treatment strategies of CRC. Additionally, there is a brief discussion on the CRC development pathways and recommendations for preventing and treating CRC.

Lack of knowledge is the leading key for the growing cervical cancer incidents in Bangladesh: A population based, cross-sectional study.

INTRODUCTION: Cervical cancer is the second most common gynecological cancer in Bangladesh. Lack of awareness of screening methods, risk factors, and symptoms may lead to presenting most cervical cancers at an advanced stage. We investigated knowledge and awareness of cervical cancer (CCa) among females at the Sheikh Hasina Medical College (SHMC) of Tangail district in Bangladesh. METHODS: A cross sectional survey was conducted to collect data via a structured questionnaire from SHMC during the period of February 2019 to January 2020. Data on socio-demographic characteristics and knowledge of cervical cancer were collected. Multivariable logistic regression models were used to identify factors associated with having heard and knowledge of cervical cancer. A p-value <0.05 was considered significant. RESULT: Of all the interviews conducted, only 45.2% (493/1090) had heard of cervical cancer as a disease. Women were more likely to be aware of CCa if they were lived in urban areas, had higher education (university level education) and belong to high income families. The study revealed evidence of significant association between marital, literacy, residence and socio-economic status with women's knowledge on cervical cancer (p< 0.05). CONCLUSION: This study serves to highlight that there was impoverished knowledge about cervical cancer among Bangladeshi women. Hence, this indicates the government should take proper steps to raise awareness and knowledge levels via educational programs and health counseling.

The scenario of knowledge, attitude and practice of the Bangladeshi population towards thalassemia prevention: A nationwide study.

Thalassemia is one of the most common life-threatening yet preventable congenital hemoglobin disorders especially in South Asian regions like Bangladesh. It has become a rising public health concern for Bangladesh as 6-12% of the population are carriers and many of them are unaware of it. The purpose of the study is to inspect the knowledge and attitude towards thalassemia among the general people of Bangladesh. A cross-sectional survey was conducted in eight administrative regions of Bangladesh between January and October of 2020. A structured questionnaire was designed to collect information about thalassemia and socio-demographic characteristics. Multivariate logistic regression models were used to identify factors associated with knowledge of thalassemia. A p-value <0.05 was considered significant. Of the 1,248 participants, only 47.4% had heard of thalassemia. Half of the participants who heard about the disease had no idea that thalassemia was not a transfusion transmitted disease. Only 49.8% of participant correctly identified consanguineous marriages as an important risk factor. Majority of them knew that marriage between two carriers can lead to a child with thalassemia major. About 72.5% knew that blood tests are a diagnosis method to determine thalassemia. Among the socio-demographic variables, the level of education of the respondents was identified as an independent predictor for knowledge (p<0.05) on thalassemia. For example, graduate (aOR: 24.88; 95% CI: 6.238-99.232) or post-graduate (aOR: 33.18; 95% CI: 7.864-140.001) participants were more aware of thalassemia than non-graduates. However, about 68.2% of the participants showed a positive attitude towards premarital screening of themselves or their family members and 85.3% were willing to donate blood to thalassemia patients. The study shows that there is a need to disseminate the information on thalassemia since the knowledge gap is huge among people. These findings will strengthen the implementation of thalassemia major awareness through educational programs, health counseling, premarital screening and campaigning.

Evaluation of knowledge, awareness and attitudes towards breast cancer risk factors and early detection among females in Bangladesh: A hospital based cross-sectional study.

BACKGROUND: Breast cancer (BCa) is a leading cause of mortality among women in Bangladesh. Many young women in Bangladesh have poor knowledge about breast cancer screening, including risk factors, warning signs/symptoms, diagnosis and early detection. We investigated awareness about breast cancer risk factors as a screening tool among women at the Sheikh Hasina Medical College (SHMC) of Tangail district in Bangladesh. METHODS: A cross sectional survey was conducted to collect data via a structured questionnaire from SHMC during the period of February to December 2019. A total of 1,007 participants (aged 33.47 (±12.37 years)) was considered for data analysis. RESULTS: Of the 1,007 women, about 50% were knowledgeable about the risk factors. Pain in the breast was identified as the most commonly warning sign/symptom of breast cancer. Only 32.2% of respondents knew at least one breast cancer screening method. The mean knowledge was scored 3.43 ± 2.25 out of a total possible score of 8. Awareness of BCa was associated with residence, family history of breast cancer, marital, literacy and socio-economic status (p <0.05). Only 14.7% of women who knew about BSE said they were conducting regular breast self-examination. Unmarried women (aOR: 2.971; 95% CI: 1.108-7.968) were more likely to have performed BSE compared to married women (p <0.05). CONCLUSION: Although most participants were aware of breast cancer; knowledge about risk factors, warning signs/symptoms, early diagnosis and detection was relatively poor. Knowledge about performing BSE was particularly low. This highlights the importance of increasing awareness about breast cancer risk factors and early detection among young women in Bangladesh.

Pathogenic genetic variants from highly connected cancer susceptibility genes confer the loss of structural stability.

Genetic polymorphisms in DNA damage repair and tumor suppressor genes have been associated with increasing the risk of several types of cancer. Analyses of putative functional single nucleotide polymorphisms (SNP) in such genes can greatly improve human health by guiding choice of therapeutics. In this study, we selected nine genes responsible for various cancer types for gene enrichment analysis and found that BRCA1, ATM, and TP53 were more enriched in connectivity. Therefore, we used different computational algorithms to classify the nonsynonymous SNPs which are deleterious to the structure and/or function of these three proteins. The present study showed that the major pathogenic variants (V1687G and V1736G of BRCA1, I2865T and V2906A of ATM, V216G and L194H of TP53) might have a greater impact on the destabilization of the proteins. To stabilize the high-risk SNPs, we performed mutation site-specific molecular docking analysis and validated using molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) studies. Additionally, SNPs of untranslated regions of these genes affecting miRNA binding were characterized. Hence, this study will assist in developing precision medicines for cancer types related to these polymorphisms.

Knowledge, awareness and preventive practices of dengue outbreak in Bangladesh: A countrywide study.

BACKGROUND: Dengue, the mosquito borne disease has become a growing public health threat in Bangladesh due to its gradual increasing morbidity and mortality since 2000. In 2019, the country witnessed the worst ever dengue outbreak. The present study was conducted to characterize the socio-economic factors and knowledge, attitude and practice (KAP) status towards dengue among the people of Bangladesh. METHOD: A cross-sectional study was conducted with 1,010 randomly selected respondents from nine different administrative regions of Bangladesh between July and November 2019. A structured questionnaire was used covering socio-demographic characteristics of the participants including their knowledge, awareness, treatment and practices regarding dengue fever. Factors associated with the knowledge and awareness of dengue were investigated separately, using multivariable logistic regression. RESULTS: Although majority (93.8%) of the respondents had heard about dengue, however, they had still misconceptions about Aedes breeding habitat. Around half of the study population (45.7%) had mistaken belief that Aedes can breed in dirty water and 43.1% knew that Aedes mosquito usually bites around sunrise and sunset. Fever indication was found in 36.6% of people which is the most common symptom of dengue. Among the socio-demographic variables, the level of education of the respondents was identified as an independent predictor for both knowledge (p<0.05) and awareness (p<0.05) of dengue. The preventive practice level was moderately less than the knowledge level though there was a significant association (p<0.05) existed between knowledge and preventive practices. Our study noted that TV/Radio is an effective predominant source of information about dengue fever. CONCLUSION: As dengue is emerging in Bangladesh, there is an urgent need to increase health promotion activities through campaigns for eliminating the misconception and considerable knowledge gaps about dengue.

Designing potential siRNA molecule for the nucleocapsid(N) gene silencing of different SARS-CoV-2 strains of Bangladesh: Computational approach.

SARS-CoV-2 is a single-stranded RNA (+) virus first identified in China and then became an ongoing global outbreak. In most cases, it is fatal in humans due to respiratory malfunction. Extensive researches are going to find an effective therapeutic technique for the treatment of SARS-CoV-2 infected individuals. In this study, we attempted to design a siRNA molecule to silence the most suitable nucleocapsid(N) gene of SARS-CoV-2, which play a major role during viral pathogenesis, replication, encapsidation and RNA packaging. At first, 270 complete N gene sequences of different strains in Bangladesh of these viruses were retrieved from the NCBI database. Different computational methods were used to design siRNA molecules. A siRNA molecule was built against these strains using the SiDirect 2.0 server. Using Mfold and the OligoCalc server, the siRNA molecule was tested for its secondary structure and GC material. The Clustal Omega tool was employed to evaluate any off-target harmony of the planned siRNA molecule. Herein, we proposed a duplex siRNA molecule that does not fit any off-target sequences for the gene silencing of SARS-CoV-2. To treat SARS-CoV-2 infections, currently, any effective therapy is not available. Our engineered siRNA molecule could give an alternative therapeutic approach against various sequenced SARS-CoV-2 strains in Bangladesh.

Newly designed analogues from SARS-CoV inhibitors mimicking the druggable properties against SARS-CoV-2 and its novel variants.

The emerging variants of SARS coronavirus-2 (SARS-CoV-2) have been continuously spreading all over the world and have raised global health concerns. The B.1.1.7 (United Kingdom), P.1 (Brazil), B.1.351 (South Africa) and B.1.617 (India) variants, resulting from multiple mutations in the spike glycoprotein (SGp), are resistant to neutralizing antibodies and enable increased transmission. Hence, new drugs might be of great importance against the novel variants of SARS-CoV-2. The SGp and main protease (Mpro) of SARS-CoV-2 are important targets for designing and developing antiviral compounds for new drug discovery. In this study, we selected seventeen phytochemicals and later performed molecular docking to determine the binding interactions of the compounds with the two receptors and calculated several drug-likeliness properties for each compound. Luteolin, myricetin and quercetin demonstrated higher affinity for both the proteins and interacted efficiently. To obtain compounds with better properties, we designed three analogues from these compounds and showed their greater druggable properties compared to the parent compounds. Furthermore, we found that the analogues bind to the residues of both proteins, including the recently identified novel variants of SARS-CoV-2. The binding study was further verified by molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) approaches by assessing the stability of the complexes. MD simulations revealed that Arg457 of SGp and Met49 of Mpro are the most important residues that interacted with the designed inhibitors. Our analysis may provide some breakthroughs to develop new therapeutics to treat the proliferation of SARS-CoV-2 in vitro and in vivo.

Molecular characterization and functional annotation of a hypothetical protein (SCO0618) of Streptomyces coelicolor A3(2).

Streptomyces coelicolor is a gram-positive soil bacterium which is well known for the production of several antibiotics used in various biotechnological applications. But numerous proteins from its genome are considered hypothetical proteins. Therefore, the present study aimed to reveal the functions of a hypothetical protein from the genome of S. coelicolor. Several bioinformatics tools were employed to predict the structure and function of this protein. Sequence similarity was searched through the available bioinformatics databases to find out the homologous protein. The secondary and tertiary structure were predicted and further validated with quality assessment tools. Furthermore, the active site and the interacting proteins were also explored with the utilization of CASTp and STRING server. The hypothetical protein showed the important biological activity having with two functional domain including POD-like_MBL-fold and rhodanese homology domain. The functional annotation exposed that the selected hypothetical protein could show the hydrolase activity. Furthermore, protein-protein interactions of selected hypothetical protein revealed several functional partners those have the significant role for the bacterial survival. At last, the current study depicts that the annotated hypothetical protein is linked with hydrolase activity which might be of great interest to the further research in bacterial genetics.

Pathway based therapeutic targets identification and development of an interactive database CampyNIBase of Campylobacter jejuni RM1221 through non-redundant protein dataset.

The bacterial species Campylobacter jejuni RM1221 (CjR) is the primary cause of campylobacteriosis which poses a global threat for human health. Over the years the efficacy of antibiotic treatment is becoming more fruitless due to the development of multiple drug resistant strains. Therefore, identification of new drug targets is a valuable tool for the development of new treatments for affected patients and can be obtained by targeting essential protein(s) of CjR. We conducted this in silico study in order to identify therapeutic targets by subtractive CjR proteome analysis. The most important proteins of the CjR proteome, which includes chokepoint enzymes, plasmid, virulence and antibiotic resistant proteins were annotated and subjected to subtractive analyses to filter out the CjR essential proteins from duplicate or human homologous proteins. Through the subtractive and characterization analysis we have identified 38 eligible therapeutic targets including 1 potential vaccine target. Also, 12 potential targets were found in interactive network, 5 targets to be dealt with FDA approved drugs and one pathway as potential pathway based drug target. In addition, a comprehensive database 'CampyNIBase' has also been developed. Besides the results of this study, the database is enriched with other information such as 3D models of the identified targets, experimental structures and Expressed Sequence Tag (EST) sequences. This study, including the database might be exploited for future research and the identification of effective therapeutics against campylobacteriosis. URL: (http://nib.portal.gov.bd/site/page/4516e965-8935-4129-8c3f-df95e754c562#Banner).