Exploring the promising application of Be12O12 nanocage for the abatement of paracetamol using DFT simulations.

The removal of paracetamol from water is of prime concern because of its toxic nature in aquatic environment. In the present research, a detailed DFT study is carried out to remove paracetamol drug from water with the help of Be12O12 to eliminate the related issues. Three different geometries (CMP-1, CMP-2, CMP-3,) are obtained with the highest adsorption energies value (Eads) of - 31.2316 kcal/mol for CMP-3 without any prominent structural change. It is observed from the study that O atom from the carbonyl group (C=O) and H atom from O-H group successfully interact with O and Be atoms of the nanocage respectively. Natural bonding orbitals analysis reveals charge transfer to paracetamol drug from Be12O12 nanocage with maximum charge transfer of - 0.159 e for CMP-3 with bond angle of 1.65 Å confirming the stability of the CMP-3 among the optimized complexes. The quantum theory of atoms in molecule concludes that the interaction between paracetamol drug molecule and Be12O12 is purely closed-shell weak electrostatic in nature in CMP-1 and CMP-3 and shared interaction in CMP-2. The thermodynamics analysis witnesses that the process is exothermic and spontaneous. The regeneration study reveals the reversible nature of the adsorbent. The overall study presents Be12O12 nanocage as a potential adsorbent and may be used in future for the purification of water from a number of emerging pollutants.

Synthesis, Characterization, DPPH Radical Scavenging, Urease Enzyme Inhibition, Molecular Docking Simulation, and DFT Analysis of Imine Derivatives of 4-formylpyridine with Selective Detection of Cu+2 Ions.

This study aimed to prepare three imine derivatives (1, 2, and 3) via a condensation reaction of phenyl hydrazine, 2-hydrazino pyridine, and 4-methoxy aniline with 4-formyl pyridine. Electron impact mass spectrometry (EIMS), proton nuclear magnetic resonance (1H-NMR), ultraviolet-visible (UV-Vis) and Fourier transform infrared (FTIR) spectroscopy were utilized for the characterization. The chemosensing properties of [4((2-phenyl hydrazono)methyl) pyridine] (1), [2-(2-(pyridin-4-ylmethylene)hydrazinyl) pyridine] (2), and [4-methoxy-N-yl methylene) aniline] (3) imino bases have been explored for the first time in aqueous media. The photophysical properties of chemosensors (1, 2, and 3) were examined by various cations (Na+, NH4+, Ba+2, Ni+2, Ca+2, Hg+2, Cu+2, Mg+2, Mn+2, and Pd+2). The chemosensor (1) showed very selective binding capability with copper ions at low concentrations (20 µM) without the influence of any other mentioned ions. The maximum complexation was noted with Cu+2 and 1 at pH between 7 to 7.5. The stoichiometry binding ratio between chemosensor (1) and Cu+2 was determined by Job's plot and it was found to be 1:2. The current study explored the use of these Schiff bases for the first time as heterocyclic chemosensors. DPPH radical scavenging, urease enzyme inhibition activities, molecular docking simulation, and density functional theory (DFT) analysis of compounds 1, 2, and 3 were also conducted.

Manifestation of pityriasis rosea and pityriasis rosea-like eruptions after Covid-19 vaccine: A systematic review.

BACKGROUND: After introducing Covid-19 vaccines, a few side effects were reported, pityriasis rosea being one of them. Therefore, this study will systematically review its manifestation afteradministration. METHODS: Databases were searched, covering a timeline from December 1, 2019 to February 28, 2022. Data were independently extracted and accessed for bias. SPSS statistical software version 25 was used for appropriate inferential statistics. RESULTS: Thirty-one studies were included for data extraction after screening following the eligibility criteria. A total of 111 people were identified to have developed pityriasis rosea or pityriasis rosea-like eruptions after vaccination, out of which 36 (55.38%) were female. The average age of incidence was calculated to be 44.92 years, and 63 (62.37%) people presented after administration of the first dose. It was found popularly in the trunk area, either asymptomatically or with mild symptoms. Meantime the onset, was 8.58 days, and meantime it took to recover, was 6.44 weeks. CONCLUSION: The association between pityriasis rosea and pityriasis rosea-like eruptions after Covid-19 vaccines was established, but given the scarcity of studies, there is a need to conduct different clinical trials to confirm this association further and study the etiology and mechanism of the disease.

In silico study of novel marine alkaloid jolynamine and other marine compounds via molecular docking, MM-GBSA binding energy prediction, ADMET evaluation, and molecular dynamics simulation.

In this research article bacterial (Escherichia coli and Pseudomonas aeruginosa) and fungal (Aspergillus niger and Candida albicans) enzymes are used for molecular docking of novel marine alkaloid jolynamine (10) and six marine natural compounds. Till date, no computational studies have been reported. In addition, MM/GBSA analysis is conducted for estimation of binding free energies. Furthermore, ADMET physicochemical properties were explored to understand the drug likeness property of compounds. In silico results showed that jolynamine (10) has more negative predicted binding energy among natural products. The ADMET profile of all compounds accepted the Lipinski rule and jolynamine also showed negative MM/GBSA binding free energy. Moreover, MD simulation was subjected to check structure stability. The outcomes of MD simulation of jolynamine (10) showed structure stability over 50 ns simulation. This study will hopefully facilitate the finding of other natural products and expedite the drug discovery process to screen drug like chemical compounds.

Molecular docking studies of isolated marine natural products against α-chymotrypsin.

The α-chymotrypsin is widely present in the digestive system of prokaryotes and eukaryotes that helps in the digestion by the hydrolysis of the peptide bond. It is serine protease enzyme (E.C. 3.4.21.1) and involves in many biological processes as well as in pancreatic disorders. In the previous study, marine red alga namely Jolyna laminariodes was used for the isolation of succinylanthranilic acid ester (2). Further, analogues were synthesised from anthranilic acid by using succinic anhydride, maleic anhydride and glutaric anhydride into corresponding dicarboxylic acids and further into acid ester including succinylanthranilic acid (1), succinylanthranilic acid ester (2), maleinylanthranilic acid (3), maleinylanthranilic acid ester (4), glutarnylanthranilic acid (5) and glutarnylanthranilic acid ester (6). For all natural products analogues percent inhibition against α-chymotrypsin have been calculated. In this study, molecular docking is used to estimate the binding energy of natural product analogues against α-chymotrypsin enzyme. The docking energies are in good agreement with experimental findings.

Drug repositioning against COVID-19: a first line treatment.

COVID-19 disease caused by the SARS-CoV-2 virus has shaken our health and wealth foundations. Although COVID-19 vaccines will become available allowing for attenuation of disease progression rates, distribution of vaccines can create other challenges and delays. Hence repurposed drugs against SARS-CoV-2 can be an attractive parallel strategy that can be integrated into routine clinical practice even in poorly-resourced countries. The present study was designed using knowledge of viral pathogenesis and pharmacodynamics of broad-spectrum antiviral agents (BSAAs). We carried out the virtual screening of BSAAs against the SARS-CoV-2 spike glycoprotein, RNA dependent RNA polymerase (RdRp), the main protease (Mpro) and the helicase enzyme of SARS-CoV-2. Imatinib (a tyrosine kinase inhibitor), Suramin (an anti-parasitic), Glycyrrhizin (an anti-inflammatory) and Bromocriptine (a dopamine agonist) showed higher binding affinity to multiple targets. Further through molecular dynamics simulation, critical conformational changes in the target protein molecules were revealed upon drug binding which illustrates the favorable binding conformations of antiviral drugs against SARS-CoV-2 target proteins. The resulting drugs from the present study in combination and in cocktails from the arsenal of existing drugs could reduce the translational distance and could offer substantial clinical benefit to decrease the burden of COVID-19 illness. This also creates a roadmap for subsequent viral diseases that emerge.Communicated by Ramaswamy H. Sarma.

Relative assessment of different statistical instruments and measures for the prediction of promising outcomes using docking, virtual screening and ADMET analysis against HIV-RT.

Reverse transcriptase is the most therapeutic target for the discovery of novel, potent, and non-toxic new anti-retroviral drugs. In the present work, various docking software such as Sybyl Surflex-Dock, OpenEye FRED, and Hermes GOLD were evaluated for their efficiency to reproduce known cognate inhibitors' conformations. Three metrics were used and compared to assess the performance of the applied scoring functions, i.e. enrichment factor, receiver operating characteristic (ROC) curves, and Bedroc analysis. Twelve different scoring functions of three softwares were used to assess their ability to rank the cognate ligand within the active site of its proteins. The extensive virtual screening task was performed on eight crystal structures, and the performance of docking and scoring was assessed by their ability to efficiently detect known active compounds enriched in the top-ranked of the list among a randomly selected dataset of the ten thousand compounds of the NCI database. The effectiveness of post-docking relaxation in Surflex was also evaluated. The top 20, 50, and 100 compounds were selected based on consensus scoring functions from all 48 proteins with different ligand complexes. Further, the shortlisted leads were subjected to ADMET via using Discovery Studio. The results further implicate the importance of various statistical tools that should be followed before large-scale virtual screening for the drug discovery process. In silico results demonstrating the experiment was successful. The study of the research covers the combinatorial in silico techniques such as benchmarking of the softwares and scoring functions, statistical tools applied for screening and different conformations of HIV-RT crystal structures for virtual screening with rigid and flexible molecular docking and molecular dynamics simulation approach. This study reveals a clear roadmap to identify novel scaffolds against HIV-RT for antiretroviral therapy, thus providing the remedial solutions of HIV related infections and other diseases caused by malfunctioning of the target protein.Communicated by Ramaswamy H. Sarma.

In vitro Synthesis, Structure Elucidation, and Antioxidant Properties of Platinum(IV)-hydrazide Complexes: Molecular Modeling of Free- Hydrazides Suggested as Potent Lipoxygenase Inhibitor.

BACKGROUND: A combination of biologically active ligand and metal in one molecule may increase the activity and reduce the toxicity. OBJECTIVES: In this study, the synthesis and characterization of platinum(IV) complexes with bioactive hydrazide ligands are discussed. METHOD: Elemental analysis, conductivity measurements, and spectroscopic studies were used to elucidate the structure of complexes. RESULTS: Our study suggests that hydrazide ligands coordinate with Pt(IV) in a bidentate fashion. The platinum(IV) complexes have octahedral geometry with a metal to ligand ratio of 1:2. Hydrazide ligands were coordinated with central metal platinum(IV) by oxygen of carbonyl group and nitrogen of primary amine. Synthesized complexes exhibited variable DPPH radical scavenging and lipoxygenase inhibition activity. Furthermore, it is also found that Pt(IV)-hydrazide complexes are more potent superoxide and nitric oxide radical scavengers than their uncoordinated hydrazide ligands, while in the case of lipoxygenase enzyme inhibition, some of the free hydrazide ligands are more active than their respective Pt(IV) complexes. In silico docking technique explores molecular interactions of synthesized ligands in the active site of the lipoxygenase enzyme. Predicted docking energies are in good agreement with experimental data suggesting that in silico studies might be useful for the discovery of therapeutic candidates. CONCLUSION: Structure-function relationship demonstrates that the radical scavenging and enzyme inhibition activities of the Pt(IV) compounds are affected by the nature of the ligand, position of substituent, electronic and steric effects. However, electronic factors seem to play a more important role than other factors.

Perception, Willingness, Barriers, and Hesitancy Towards COVID-19 Vaccine in Pakistan: Comparison Between Healthcare Workers and General Population.

Background Vaccine hesitancy has been a huge challenge in controlling preventable diseases. With the emergence of coronavirus disease 2019 (COVID-19) vaccines, it is vital to know their acceptance rates among the masses. No comparative data is available on the current subject from Pakistan yet. Therefore, this study aimed to evaluate the acceptance of a potential COVID-19 vaccine among the general population and healthcare workers (HCWs) of Pakistan, along with their perceptions and barriers to acceptance. Methods An online cross-sectional study was carried out in Pakistan from December 19, 2020, to January 10, 2021, using convenience sampling. A self-administered questionnaire consisting of 31 items was distributed after informed consent. Inclusion criteria consisted of HCWs and non-HCWs (general population) aged 18 years and above, residing in Pakistan. All analyses were done using Statistical Package for Social Sciences (SPSS) version 23.0 (IBM Corp., Armonk, NY, USA). Chi-square and T-test were used and a p-value of less than 0.05 was considered significant for all cases. Results Of the 404 respondents (n=196 general population and n=208 HCWs), 73.5% were willing to get a proven, safe, and effective COVID-19 vaccine if it was free of cost. This was reduced to only 64.3% if the vaccine was not free and had to be paid for. A total of 168 (41.6%) participants agreed to get vaccinated immediately, while 149 (36.9%) participants concurred to get it on a delayed basis. Eighty-seven (21.5%) participants refused to receive the COVID-19 vaccine, amongst which a significant majority (p<0.001) of the participants were from the general population. Doctors or scientists/scholarly journals were found to be the most trusted source of information (67.6%; n=273), while fear of unknown side effects (45.5%; n=184) was found to be the most common barrier towards COVID-19 vaccination. More than half (53.5%) participants believed that the vaccine is safe, effective, and has minimal side effects, amongst which a significantly large fraction (p<0.001) belonged to the HCWs. Conclusion The acceptance rate of a safe, effective, proven, and free COVID-19 vaccine was 73.5%. The fear of unknown side effects was the most common barrier to COVID-19 vaccine uptake. The general population demonstrated less knowledge, more false perceptions, and barriers to COVID-19 vaccine. Adequate measures should be taken to educate the masses about the COVID-19 vaccine, and its safety, and further studies are required.

Sexual dysfunction: Prevalence and relationship with depression and other socio-demographic factors among the type 2 diabetic women of Pakistan.

OBJECTIVE: To find the association between sexual dysfunction and depressive symptoms among type 2 diabetic women. METHODS: The cross-sectional study was conducted at the Military Hospital, Rawalpindi, Pakistan, from November 2017 to October 2018, and comprised diabetic women reporting for routine follow-up. Female sexual function index was used to assess the sexual function of the subjects. The presence of depressive symptoms was assessed using the Beck depressive inventory-II. Relationship of age, duration of diabetes, depression, education, level of family income and type of treatment was assessed with sexual dysfunction. Data was analysed using SPSS 23. RESULTS: Of the 250 subjects, 104(41.6%) were aged <40 years. Overall, 89(35.6%) women had no sexual problem, while 161(64.5%) had significant dysfunction. Also, 179(71.6%) patients had depressive symptoms, while 69(28.4%) were negative on depression screening. Increasing age and presence of depressive symptoms had significant association with sexual dysfunction (p<0.05). CONCLUSION: The prevalence of sexual dysfunction was found to be high among diabetic women. Female diabetic patients with increasing age should also be screened regularly for psycho-sexual problems.

Surveillance of molecular markers of antimalarial drug resistance in Plasmodium falciparum and Plasmodium vivax in Federally Administered Tribal Area (FATA), Pakistan.

This molecular epidemiological study was designed to determine the antimalarial drug resistance pattern, and the genetic diversity of malaria isolates collected from a war-altered Federally Administered Tribal Area (FATA), in Pakistan. Clinical isolates were collected from Bajaur, Mohmand, Khyber, Orakzai and Kurram agencies of FATA region between May 2017 and May 2018, and they underwent DNA extraction and amplification. The investigation of gene polymorphisms in drug resistance genes (dhfr, dhps, crt, and mdr1) of Plasmodium falciparum and Plasmodium vivax was carried out by pyrosequencing and Sanger sequencing, respectively. Out of 679 PCR-confirmed malaria samples, 523 (77%) were P. vivax, 121 (18%) P. falciparum, and 35 (5%) had mixed-species infections. All P. falciparum isolates had pfdhfr double mutants (C59R+S108N), while pfdhfr/pfdhps triple mutants (C59R+S108N+A437G) were detected in 11.5% of the samples. About 97.4% of P. falciparum isolates contained pfcrt K76T mutation, while pfmdr1 N86Y and Y184F mutations were present in 18.2% and 10.2% of the samples. P. vivax pvdhfr S58R mutation was present in 24.9% of isolates and the S117N mutation in 36.2%, while no mutation in the pvdhps gene was found. Pvmdr1 F1076L mutation was found in nearly all samples, as it was observed in 98.9% of isolates. No significant anti-folate and chloroquine resistance was observed in P. vivax; however, mutations associated with antifolate-resistance were found, and the chloroquine-resistant gene has been observed in 100% of P. falciparum isolates. Chloroquine and sulphadoxine-pyrimethamine resistance were found to be high in P. falciparum and low in P. vivax. Chloroquine could still be used for P. vivax infection but need to be tested in vivo, whereas a replacement of the artemisinin combination therapy for P. falciparum appears to be justified.

Protective role of TIRAP functional variant against development of coronary artery disease.

Coronary artery disease (CAD) is the leading cause of sudden death worldwide. Inflammation is proved to be an important player in development of the CAD. Inflammation is directly regulated by the Toll like receptors (TLRs). Susceptibility of CAD is influenced by genetic variations within TLRs and the proteins involved in its signaling cascade. The TIRAP/MAL {TIR domain containing adaptor protein / MyD88 (myeloid differentiation primary response gene 88) adaptor-like} exhibits maximum genetic variations of all adaptor proteins involved in TLR signaling cascade. Susceptibility to a number of diseases can be influenced due to presence of S180L single nucleotide polymorphism (SNP) of TIRAP/MAL. This study was conducted to investigate the functional role of this well characterized S180L polymorphism on susceptibility to CAD among Pakistani patients. A total of 146 Pakistani CAD patients and 147 controls were genotyped by Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) and the data was analyzed by using 2-tailed Chi square (x2 ) test. The p value ≤ 0.05 was considered to be significant. Significantly high frequency of homozygous L180L genotype was observed among healthy subjects as compared to the CAD patients [24 (16%) vs 7 (5%); x2 11.85; p = 0.003]. Moreover, the allele frequency of the minor allele; 180L was observed to be significantly higher among controls than the CAD patients, having same direction of association [156 (53%) vs 131 (45%); OR (95% CI) = 0.7198 (0.520-0.996); p < 0.05). Our results indicate that protective effect of L180L; a coding variant of TIRAP/MAL against CAD is discernible.

Molecular docking, simulation and MM-PBSA studies of nigella sativa compounds: a computational quest to identify potential natural antiviral for COVID-19 treatment.

Nigella sativa or black seed is used as a medicinal plant around the globe. Oil and seeds have a long tradition of folklore use in various medicinal and food systems. The conventional therapeutic use of Nigella sativa, in different ways, has been reported in several studies to treat different diseases including influenza, headache, hypertension, diabetes, inflammation, eczema, fever, cough, asthma, bronchitis, and fever. Based on previously reported potential therapeutic uses of N. sativa compounds, and keeping in mind the dire need of time for the development of potent antiviral, a combined docking, ADMET properties calculation, molecular dynamics, and MM-PBSA approaches were applied in the current study to check the therapeutic potentials of N. sativa chief constituents against COVID-19. Among the studied compounds, we found that dithymoquinone (DTQ), with binding affinity of -8.6 kcal/mol compared to a positive control (chloroquine, -7.2 kcal/mol) , has the high potential of binding at SARS-CoV-2:ACE2 interface and thus could be predicted as a plausible inhibitor to disrupt viral-host interactions. Molecular dynamics simulation of 100 ns well complemented binding affinity of the compound and revealed strong stability of DTQ at the docked site. Additionally, MM-PBSA also affirms the docking results. Compound DTQ of the present study, if validated in wet lab experiments, could be used to treat COVID-19 and could serve as a lead in the future for development of more effective natural antivirals against COVID-19. Communicated by Ramaswamy H. Sarma.

Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H.

Hereditary spastic paraplegias (HSPs) are a diverse class of neurodegenerative disorders that mainly affect the corticospinal tract of the body and result in various clinical conditions such as lower limb spasticity and muscle weakness in the lower extremities. Worldwide, more than 70 chromosomal loci/genes have been reported to be associated with HSPs, out of which, six genes viz., ATL1, FA2H, GJC2, AP4E1, ALDH18A1 and ATP13A2 have been mapped in Pakistani families. In the present genetic study, we report on a large consanguineous Pakistani family with a complex form of HSP segregating with a 18 bp deletion in the first exon of the Fatty Acid 2-Hydroxylase (FA2H) gene (NM_024306.5:c.159_176del). The identified in-frame deletion results in loss of six amino acids (p.Arg53_Ile58del) within the cytochrome B5 domain of the protein. FA2H is required for alpha-hydroxylation of free fatty acids to form alpha-hydroxylated sphingolipids. Its cytochrome b5-like heme-binding domain, which spans from residues 15 to 85, imparts the redox activity to FA2H. This mutation has previously been reported in a Pakistani family presenting with a similar form of complex HSP. Together with our findings the pathogenic role of the observed variant is further supported. Mutation studies on additional Pakistani families for FA2H will further elucidate its mutational spectrum, which may help in developing a prenatal diagnostic test for Khyber Pakhtunkhwa resident Pakistani families.

Viroinformatics approach to explore the inhibitory mechanism of existing drugs repurposed to fight against COVID-19.

The rapid breakout of the coronavirus disease of 2019 (COVID-19) has been declared pandemic with serious global concern due to high morbidity and mortality. As we enter the phase beyond limitations there is an urgent need for explicit treatment against COVID-19. To face this immediate global challenge, drug development from scratch is a lengthy process and unrealistic to conquer this battle. Drug repurposing is an emerging and practical approach where existing drugs, safe for humans, are redeployed to fight this harder to treat disease. A number of multi clinical studies have repurposed combined cocktail (remdesivir + chloroquine and favipiravir + chloroquine) to be effective against COVID-19. However, the exact mechanistic aspect has not yet been revealed. In the present study, we have tried to decipher the mechanistic aspects of existing medicines at the viral entry and replication stage via the structural viroinformatics approach. Here we implied the molecular docking and dynamic simulations with emphasis on the unique structural properties of host receptor angiotensin-converting enzyme 2 (ACE2), SARS-CoV2 spike protein and RNA dependent RNA polymerase enzyme (RdRp) of the SARS-CoV2. Deep structural analysis of target molecules exposed key binding residues and structural twists involved in binding with important pharmacophore features of existing drugs [(7-chloro-N-[5-(diethylamino)pentan-2-yl]quinolin-4-amine (chloroquine),N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) (SSAA09E2), 2-ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5-cyano-3 (remdesivir) and 6-Fluor-3-oxo-3,4-dihydro-2-pyrazincarboxamid (favipiravir)]. It is evident from this structural informatics study that combo of chloroquine + SSAA09E2 with remdesivir or favipiravir could significantly restrain the virus at the entry and replication stage. Thus, drug repurposition is an attractive approach with reduced time and cost to treat COVID-19, we don't have enough time as the whole world is lockdown and we are in urgent need of an obvious therapeutics' measures.

Computational Overview of Mycobacterial Thymidine Monophosphate Kinase.

Tuberculosis (TB) ranks among the diseases with the highest morbidity rate with significantly high prevalence in developing countries. Globally, tuberculosis poses the most substantial burden of mortality. Further, a partially treated tuberculosis patient is worse than untreated; they may lead to standing out as a critical obstacle to global tuberculosis control. The emergence of multi-drug resistant (MDR) and extremely drug-resistant (XDR) strains, and co-infection of HIV further worsen the situation. The present review article discusses validated targets of the bacterial enzyme thymidine monophosphate kinase (TMPK). TMPKMTB enzyme belongs to the nucleoside monophosphate kinases (NMPKs) family. It is involved in phosphorylation of TMP to TDP, and TDP is phosphorylated to TTP. This review highlights structure elucidation of TMP enzymes and their inhibitors study on TMP scaffold, and it also discusses different techniques; including molecular docking, virtual screening, 3DPharmacophore, QSAR for finding anti-tubercular agents.

Characterization of the interactions between coumarin-derivatives and acetylcholinesterase: Examination by NMR and docking simulations.

Alzheimer's disease (AD) is one of the most common forms of dementia and a significant threat to the elderly populations, especially in the Western world. The rapid hydrolysis of the principal neurotransmitter into choline and acetate by acetylcholinesterase (AChE) at synapses causes the loss of cognitive response that becomes the real cause of AD. Therefore, inhibition of AChE is the most fundamental therapy among currently available treatments for AD. In this context, we designed and performed molecular recognitions studies of coumarin-based inhibitors towards AChE. STD NMR and Tr-NOESY applications were utilized to evaluate the binding epitope, the dissociation constant (KD) and bound conformations of these inhibitors within this inhibitor-AChE complex. Compound 1, which has a similar inhibition activity to tacrine (a current drug) led in this study as a stronger binder with KD = 30 µM ,even greater than tacrine (KD = 140 µM). Moreover, docking simulations mimic NMR results and provided evidence of synchronizing binding of compound 1 with three sites; the peripheral anionic site, the bottom of the gorge, and the catalytic site. Therefore, we envisioned from our experimental and theoretical results that coumarin-based inhibitors containing a piperidinyl scaffold might be a potential drug candidates for AD in the future.

Binding site identification and role of permanent water molecule of PIM-3 kinase: A molecular dynamics study.

The kinome is a protein kinase complement of the human genome, categorized as serine/threonine and tyrosine kinases. These kinases catalyze phosphorylation reaction by using ATP as phosphoryl donor. Proviral Integration Site for Moloney Murine Leukemia Virus (PIM) kinase encodes serine/threonine protein kinases that recognized as proto-oncogene, responsible for rapid growth of cancerous cells. It is implicated in cell survival and function via cell cycle progression and its metabolism. PIM-3, sub-member of PIM kinases is a proto-oncogene, its overexpression inhibits apoptosis, and results in progression of hepatocellular carcinoma. PIM-3 is considered as a promising drug target but attempts to develop its specific inhibitors is slowed down due to the lack of 3D structure by any experimental technique. In silico techniques generally facilitate scientist to explore hidden structural features in order to improve drug discovery. In the present study, homology modeling, molecular docking and MD simulation techniques were utilized to explore the structure and dynamics of PIM-3 kinase. Induction of water molecules during molecular docking simulation explored differences in the hinge region between PIM-1 and PIM-3 kinases that may be responsible for specificity. Furthermore, role of water molecules in the active site was also explored via radial distribution function (RDF) after a 10 ns molecular dynamics (MD) simulations. Generated RDF plots exhibited the importance of water for inhibitor binding through their bridging capability that links the ligand with binding site residues.

Prevalence of High risk Human Papillomavirus in cervical dysplasia and cancer samples from twin cities in Pakistan.

INTRODUCTION: Human Papilloma Virus (HPV) is small DNA virus mostly infecting mucosa and cutaneous keratinocytes. So far, more than 200 Human papillomaviruses are known. HPV have been divided into high- and low-risk on the basis of their oncogenic potential. High risk HPV is considered to be the main etiological cause for cervical cancer. OBJECTIVE: The current study was designed to screen the local cervical cancer patients from the twin cities of Pakistan for the occurance of high risk HPV. METHODOLOGY: A total of 67 formalin fixed paraffin-embedded samples of cervical cancer biopsies were obtained from the government hospitals in Islamabad and Rawalpindi. Cervical cancer biopsies were examined for the presence of HPV DNA. Polymerase chain reaction (PCR) was used for the amplification of a region in the HPV-L1 gene for the general detection of the Papilloma virus and for the genotype specific detection of high risk HPV 16 and 18 using the GP5/GP6 primers and genotype specific primers, respectively. RESULTS: HPV DNA was detected in 59 out of 67 samples analyzed. 30 samples showed the presence of HPV16 while 22 samples were positive for HPV18. HPV subtype could not be determined in 7 samples. CONCLUSION: Our results show a strong association between HPV infection and cervical cancer among women in twin cities of Pakistan. One way to minimize the disease burden in relation to HPV infection in Pakistani population is the use of prophylactic vaccines and routine screening. An early diagnosis of HPV infection will allow better health management to reduce the risk of developing cervical cancer.

Roles for human papillomavirus type 16 l1 cysteine residues 161, 229, and 379 in genome encapsidation and capsid stability.

Human papillomavirus (HPV) capsids are formed through a network of inter- and intra-pentameric hydrophobic interactions and disulfide bonds. 72 pentamers of the major capsid protein, L1, and an unknown amount of the minor capsid protein, L2, form the structure of the capsid. There are 12 conserved L1 cysteine residues in HPV16. While C175, C185, and C428 have been implicated in the formation of a critical inter-pentameric disulfide bond, no structural or functional roles have been firmly attributed to any of the other conserved cysteine residues. Here, we show that substitution of cysteine residues C161, C229, and C379 for serine hinders the accumulation of endonuclease-resistant genomes as virions mature within stratifying and differentiating human epithelial tissue. C229S mutant virions form, but are non-infectious. These studies add detail to the differentiation-dependent assembly and maturation that occur during the HPV16 life cycle in human tissue.