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Breast cancer (BC) is the most serious and second leading cause of death in women worldwide. When breast cancer is diagnosed and treated early, the chance of long-term survival is up to 90%. On the other hand, 90% of BC patient deaths are due to metastasis and a lack of effective early diagnosis. The existing conventional chemotherapy provides negative feedback due to transportation barriers towards the action sites, multidrug resistance, poor bio-availability, non-specific delivery and systemic side effects on the healthy tissue. Syk protein Kinase has been reported in BC, as a tumor modulator, providing a pro-survival signal and also by restricting epithelial-mesenchymal transition, enhancing cell-cell interactions and inhibiting migration. In the present study, we explored the possibility of targeting BC by attenuating Syk protein Kinase. Hence, we have conjugated the hydrophobic Bendamustine (BEN) and hydrophilic Azacitidine (AZA) anticancer drugs to evaluate their efficacy against BC. The native drugs (BEN and AZA) and designed drug-drug conjugate (BEN-AZA) were docked with Syk protein. Then, the docked complex was performed for Binding Free Energy and Molecular Dynamics Simulations. Furthermore, DFT and ADME properties were carried out. The results revealed that the designed drug-drug conjugate has a better docking score, ΔGbind and admirable stability throughout the simulation when compared with native drugs. In DFT and ADME analyses, the designed drug-drug conjugate has shown good stereo electronic features and pharmaceutical relevant parameters than that of native drugs. The overall results suggested that the designed drug-drug conjugate may be a suitable candidate for BC treatment. Communicated by Ramaswamy H. Sarma

The bacterial DNA gyrase is an attractive target to identify the novel antibacterial agents. The flavonoid derivatives possess various biological activities such as antimicrobial, anti-inflammatory...

Cysteine proteases play a major role in many life processes and are the target of key drugs. The reaction mechanism of these enzymes is a complex process, which involves several steps that are divided into two main groups: acylation and deacylation. In this work, we studied the energy profile for the acylation and a part of the deacylation reaction of three different enzymes, cruzain, papain, and the Q19A-mutated papain with the benzyloxycarbonyl-phenylalanylarginine-4-methylcoumaryl-7-amide (CBZ-FR-AMC) substrate. The calculations were performed using the EVB and PDLD/S-LRA methods. The overall agreement between the calculated and observed results is encouraging and indicates that we captured the correct reaction mechanism. Finally, our finding indicates that the minimum of the reaction profile, between the acylation and deacylation steps, should provide an excellent state for the binding of covalent inhibitors.

Introduction. Acinetobacter baumannii is a critical priority pathogen listed by the World Health Organization due to increasing levels of resistance to carbapenem classes of antibiotics. It causes wound and other nosocomial infections, which can be life-threatening. Hence, there is an urgent need for the development of new classes of antibiotics. Aim. To study the interaction of carabapenems with class D beta-lactamases (oxacillinases) and analyse drug resistance by studying enzyme–substrate complexes using modelling approaches as a means of establishing correlations with the phenotypic data. Methodology. The three-dimensional structures of carbapenems (doripenem, ertapenem, imipenem and meropenem) were obtained from DrugBank and screened against class D beta-lactamases. Further, the study was extended with their variants. The variants’ structure was homology-modelled using the Schrödinger Prime module (Schrödinger LLC, NY, USA). Results. The first discovered intrinsic beta-lactamase of Acinetobacter baumannii , OXA-51, had a binding energy value of −40.984 kcal mol−1, whereas other OXA-51 variants, such as OXA-64, OXA-110 and OXA-111, have values of −60.638, –66.756 and −67.751 kcal mol−1, respectively. The free energy values of OXA-51 variants produced better results than those of other groups. Conclusions. Imipenem and meropenem showed MIC values of 2 and 8 µg ml−1, respectively against OXA-51 in earlier studies, indicating that these are the most effective drugs for treatment of A. baumannii infection. According to our results, OXA-51 is an active enzyme that shows better interactions and is capable of hydrolyzing carbapenems. When correlating the hydrogen-bonding interaction with MIC values, the predicted results are in good agreement and might provide initial insights into performing similar studies related to OXA variants or other antibiotic–enzyme-based studies.

Dengue virus (DENV) is a mosquito-borne disease that spreads in the tropics and subtropics mainly by the Aedes aegypti mosquito, infecting more than 100 million people and cause copious deaths every year in globally. As of now, no direct-acting antiviral drugs or vaccine are available to combat DENV. Therefore, identification of novel small molecules from natural origin becomes inevitable for the management of DENV fever. Here, in silicofromPadinagymnospora was analyzed for competitive binding on the active site non-structural protein NS3 proteases were selected that are potential therapeutic target for direct-acting antiviral. The fucoidan compound was docked with active site of NS3 proteases, showing good docking score and strong interaction with the catalytic dyad His51, Asp75 and Ser135 amino acids. Furthermore, Binding Free Energy was done by using prime MM/GBSA to access the binding affinity of fucoidan towards the target protein. Moreover, Molecular Dynamic Simulation was performed to evaluate the structural stability of the docked complexes. In addition, HOMO and LUMO for fucoidan phytocompound was done by DFT calculation, reveals the good chemical stability based on the energy value. The fucoidan phytocompound has satisfied all the relevant pharmacokinetic properties and also highly absorbed by the gastrointestinal tract. From the overall findings of this study, it is concluded that the fucoidan from Padinagymnospora has effectively blocked the catalytic dyad of NS3 proteases which could be considered as a potent inhibitor to control the DENV multiplication infection. Insilico approach plays vital role in the initial screening of lead molecules.

The majority of bacteria and archaea contains Toxin-Antitoxin system (TA) that codes for the stable Toxin and unstable Antitoxin components forming a complex. The Antitoxin inhibits the catalytic activities of the Toxin. In general, the Antitoxin will be degraded by the proteases leading to the Toxin activation that subsequently targets essential cellular processes, including transcription, translation, replication, cell division, and cell wall biosynthesis. The Zeta Toxin-Epsilon Antitoxin system in ESKAPE pathogen stabilizes the resistance plasmid and promotes pathogenicity. The known TA system in Acinetobacter baumannii are known to be involved in the replication and translation, however, the mechanism of Zeta Toxin-Epsilon Antitoxin in cell wall biosynthesis remains unknown. In the present study, molecular docking and molecular dynamic (MD) simulations were employed to demonstrate whether Zeta Toxin can impair cell wall synthesis in A. baumannii. Further, the degradation mechanism of Antitoxin in the presence and absence of adenosine triphosphate (ATP) molecules are explained through MD simulation. The result reveals that the cleavage of Antitoxin could be possible with the presence of ATP by displaying its response from 20 ns, whereas the Zeta Toxin/Epsilon was unstable after 90 ns. The obtained results demonstrate that Zeta Toxin is "temporarily favorable" for ATP to undergo phosphorylation at UNAG kinase through the substrate tunneling process. The study further evidenced that phosphorylated UNAG prevents the binding of MurA, the enzyme that catalyzes the initial step of bacterial peptidoglycan biosynthesis. Therefore, the present study explores the binding mechanism of Zeta Toxin/Epsilon Antitoxin, which could be beneficial for preventing cell wall biosynthesis as well as for unveiling the alternative treatment options to antibiotics.

Nanotechnology is a branch of science, which empowers innovation to discover new medical technologies, improving current diagnostic and treatment methods. The scope of nanotechnology focuses mainly on “technology transfer”, in which research aims to facilitate the application of recent nanoscience techniques to conventional medicine development methodologies. Nanomedicine is attractive to researchers who wish to target specific infectious diseases associated with poverty, which is highlighted through the many pertinent examples of recent breakthroughs in nanomedicine. An overview is provided in this study to highlight the barriers and implementation of nanomedicine for various infectious diseases in the African continent. Patient backgrounds provide the greatest of challenges for new technologies in terms of improving bioavailability and dosage. This review points out the current situation of nanomedicine in Africa and explores the possibility of how nanomedicine could improve patient drug regimens and wellbeing.

Extended spectrum β-lactamases (ESBLs) are a group of enzymes that can hydrolyze a variety of β-lactams including fourth generation cephalosporins and compromise the efficacy of all β-lactams, except cephamycins and carbapenems. In the worldwide, the ESBL group of enzymes are found widely and causes a severe infection on human health which leads to various diseases. This review primarily focusses on analyzing the prevalence and drug resistance patterns in the African continent. From the earlier reported data shown only the minimal amount of surveillance information's has been summarized with respect to antimicrobial resistance on ESBLs producing Enterobacteriaceae both in hospital and community settings. To bring the present scenario in limelight, the present study explores the prevalence of ESBL-producing Enterobacteriaceae in various countries in Africa and specifically, to identify most common ESBL genes in hospital and community. The observation was initiated with the exhaustive literature search using PubMed and other databases to broaden the study from the earlier investigations in the African countries concerned about the prevalence rate of ESBL producing Enterobacteriaceae. Further, this study was extended to review various hypothesis of the hydrolytic mechanism, which was detailed by several authors performed earlier through computational approaches. Interestingly, the ESBLs class A and D were found to be common classes in Africa, with the gene CTX-M-15 being most prevalent. Notably, the present review highlights the prevalence on individual countries in Africa and it is extremely significant to prevent the dissemination of ESBL-producing Enterobacteriaceaea. Hence, this review on surveillance will be the benchmark to enhance the research on antimicrobial resistance patterns for all classes and genes. Furthermore, explored in-sights in this paper will be helpful for the further investigations to develop quicker, cost effective, and reliable diagnostic strategies and new effective therapies.

Although high numbers of novel antibiotics are available in the market currently, it is still a challenge to treat intracellular pathogens. These therapeutic agents always need to be used in high doses, as their antibiotic concentrations are often sub-therapeutic. This is expensive and results in adverse systemic and localized side effects. The current rising threat of antibiotic resistance further complicates the treatment of intracellular pathogenic diseases. As a result, there is a crucial need for methods and systems that enable physicians to attain therapeutically effective intracellular concentrations of those antibiotics. In this scenario, the use of drug delivery systems carrying antibiotics showing targeted and effective antibacterial activity in vitro need to be considered and given due attention. Incorporating or encapsulating antibacterial drugs within these unique drug delivery systems offers better control of pharmacokinetic behavior of the active bactericidal molecule. Such new and advanced methods will replace old conventional antibiotics, which are becoming unusable due to resistance or toxicity. They are vital in rescuing the last-line therapeutic antibiotics through advancing the therapeutic index, broadening the antibiotic antimicrobial spectrum and avoiding failure due to membrane permeability problems, and thus shortening the current time required by classical treatments and reducing the extent of drug resistance. Hence, new and improved drug carriers have been established for treating intracellular pathogens, including antibiotics loaded into hydrogels, liposomes, micelles, polymeric carriers, and metal nanoparticles. This chapter focuses on the role of a drug delivery system as a potential tool against intracellular bacterial pathogens.

Cancer is one of the most common health problems and the second leading cause of death worldwide. Previous research has failed to provide convincing evidence of conventional cancer treatment strategies involving chemotherapy and surgery due to their side-effects. Recent years have witnessed burgeoning interest in theranostic nanomedicine for cancer detection and treatment. Concurrently, the extent to which phytosynthesized nanomaterials can play a role in cancer theranostics continues to be an issue of interest to researchers. There is growing empirical evidence that biogenic nanomaterials and in particular metals such as silver, gold, iron, titanium, copper, zinc, etc. can be successfully used for various biomedical applications. The current review provides perspective on the use of emerging plant-based anti-cancer green nanomaterials with a focus on their present status as well as challenges and barriers as future cancer theranostics.

Computer-aided enzyme design presents a major challenge since in most cases it has not resulted in an impressive catalytic power. The reasons for the problems with computational design include the use of nonquantitative approaches, but they may also reflect other difficulties that are not completely obvious. Thus, it is very useful to try to learn from the trend in directed evolution experiments. Here we explore the nature of the refinement of Kemp eliminases by directed evolution, trying to gain an understanding of related requirements from computational design. The observed trend in the directed evolution refinement of KE07 and HG3 are reproduced, showing that in the case of KE07 the directed evolution leads to ground-state destabilization, whereas in the case of HG3 the directed evolution leads to transition-state stabilization. The nature of the different paths of the directed evolution is examined and discussed. The present study seems to indicate that computer-aided enzyme design may require more than calculations of the effect of single mutations and should be extended to calculations of the effect of simultaneous multiple mutations (that make a few residues preorganized effectively). However, the analysis of two known evolution paths can still be accomplished using the relevant sequences and structures. Thus, by comparing two directed evolution paths of Kemp eliminases we reached the important conclusion that the more effective path leads to transition-state stabilization.