FtsZ inhibitors as a new genera of antibacterial agents.

The continuous emergence and rapid spread of a multidrug-resistant strain of bacterial pathogens have demanded the discovery and development of new antibacterial agents. A highly conserved prokaryotic cell division protein FtsZ is considered as a promising target by inhibiting bacterial cytokinesis. Inhibition of FtsZ assembly restrains the cell-division complex known as divisome, which results in filamentation, leading to lysis of the cell. This review focuses on details relating to the structure, function, and influence of FtsZ in bacterial cytokinesis. It also summarizes on the recent perspective of the known natural and synthetic inhibitors directly acting on FtsZ protein, with prominent antibacterial activities. A series of benzamides, trisubstituted benzimidazoles, isoquinolene, guanine nucleotides, zantrins, carbonylpyridine, 4 and 5-Substituted 1-phenyl naphthalenes, sulindac, vanillin analogues were studied here and recognized as FtsZ inhibitors that act either by disturbing FtsZ polymerization and/or GTPase activity. Doxorubicin, from a U.S. FDA, approved drug library displayed strong interaction with FtsZ. Several of the molecules discussed, include the prodrugs of benzamide based compound PC190723 (TXA-709 and TXA707). These molecules have exhibited the most prominent antibacterial activity against several strains of Staphylococcus aureus with minimal toxicity and good pharmacokinetics properties. The evidence of research reports and patent documentations on FtsZ protein has disclosed distinct support in the field of antibacterial drug discovery. The pressing need and interest shall facilitate the discovery of novel clinical molecules targeting FtsZ in the upcoming days.

One Health intervention for elimination of anthrax in an endemic district of Odisha: A baseline and endline study.

Background: This study was to compare a baseline and endline survey which were conducted to assess the changes in knowledge, attitude and practices about anthrax disease among the communities after One Health intervention for the elimination of human anthrax in an endemic district of Odisha. Methods: A total of 2670 respondents were interviewed during the baseline and 2511 for the endline survey using a structured questionnaire by multi-stage sampling method. Descriptive statistics were used and logistic regression was performed to estimate the relationship between the variables and knowledge of anthrax. Results: Out of the total participants in the study, males were about 76.25% in baseline and 72.08% in endline and about half of the total respondents were illiterate. Majority of the respondents had reported agriculture as their main occupation during both surveys. More than 50% of the respondents had livestock in their houses and farming was the main purpose for keeping them in both surveys. Around 20.26% of respondents knew about anthrax in baseline which raised to 53.64% after One Health intervention. Almost 21.29% of livestock owners had vaccinated their animals against anthrax disease throughout baseline, which increased to 66.5% during the endline survey. Conclusion: This study highlights a significant surge in both knowledge and practices related to anthrax within the community after the implementation of intervention packages based on the One Health approach. The outcome of our study signified the importance of One Health interventions to address the health challenges related to zoonotic diseases in tribal communities. The data could be useful for local Governments to incorporate such an approach in their health policy to eliminate human anthrax.

A Combined Approach of Pharmacophore Modeling, QSAR Study, Molecular Docking and In silico ADME/Tox Prediction of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one Analogs to Identify Potential Reverse Transcriptase Inhibitor: Anti-HIV Agents.

BACKGROUND: Reverse transcriptase is an important therapeutic target to treat AIDS caused by the Human Immunodeficiency Virus (HIV). Despite many effective anti-HIV drugs, reverse transcriptase (RT) inhibitors remain the cornerstone of the drug regimen to treat AIDS. In the present work, we have expedited the use of different computational modules and presented an easy, costeffective, and high throughput screening method to identify potential reverse transcriptase inhibitors. METHODS: A congeneric series of 4-Arylthio & 4-Aryloxy-3- Iodopyridine-2(1H)-one analogs having anti-HIV activity were subjected to structure-based 2D, 3D QSAR, Pharmacophore Modeling, and Molecular Docking to elucidate the structural properties required for the design of potent HIV-RT inhibitors. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. RESULTS: The 2D and 3D- QSAR models were developed by correlating two and three-dimensional descriptors with activity (pIC50) by sphere exclusion method and k-nearest neighbor molecular field analysis approach, respectively. The significant 2D- QSAR model developed by Partial Least Square is associated with the Sphere Exclusion method (PLS-SE), having r2 and q2 values 0.9509 and 0.8038, respectively. The 3D-QSAR model by Step Wise variable selection method (SW-kNN MFA) is more significant, which has a cross-validated squared correlation coefficient q2= 0.8509 and a non-crossvalidated correlation coefficient pred_r2= 0.8102. The pharmacophore hypothesis was developed, which comprised 5 features includes 3 aliphatic regions (Ala), 1 H-bond donor (HDr) and 1 H-bond acceptor (HAc). Docking studies of the selected inhibitors with the active site of reverse transcriptase enzyme showed hydrogen bond and π - π interaction with LYS-101, LYS-103, TYR- 181, TYR-188 and TRP-229 residues present at the active site. All the candidates with good bioavailability and ADMET drug likeliness properties. CONCLUSION: The results of the present work provide more useful information and important structural insights for the discovery, design of novel and potent reverse transcriptase inhibitors with high therapeutic windows in the future.

Identification of Antimycobacterial Agent Using In Silico Virtual Screening, ADME Prediction, Docking, and Molecular Dynamics Simulations Approach.

BACKGROUND: The widespread hazardous issue of antibiotics resistance can be overcome by the development of target based potent antibacterial agents. Filamentous temperature-sensitive mutant Z (FtsZ), a simpler structural prokaryotic homolog of eukaryotic cytoskeletal tubulin, was considered as a competent target in antibacterial drug discovery. OBJECTIVE: The purpose of the present work is to evaluate the antitubercular activity of virtual hits by funnel-shaped filtering with glide docking, followed by MM-GBSA binding energy and molecular dynamics simulation. Pharmacokinetics and biochemical activity of the computationally screened virtual hits have been studied to focus their potential to inhibit the bacterial cell division. METHODS: The docking study was performed against the crystal structure of Staphylococcus aureus and Mycobacterium tuberculosis FtsZ protein with the hits obtained from High Throughput Virtual Screening using the Glide module in Schrodinger. ADME profile and 50 ns molecular dynamics simulation studies were performed using the Schrödinger suite. The minimal inhibitory concentration of the test compounds was determined by the colorimetric method by the Resazurin Microtiter plate Assay. RESULTS: The binding of hit molecules T5427054 and 6M356S was mainly supported by van der Waals interaction and an electrostatic component of solvation energy computed by the MM-GBSA method. 50 ns MD simulation built stability and dynamic property of the best-docked complex T5427054/2Q1Y. Both the hit molecules displayed antimycobacterial activity with minimal inhibitory concentration 500 µg/mL. CONCLUSION: In this study, it is found that new screened hit molecules with better theoretical results could be preferred to use as antimycobacterial agents, and further their structural modification might be improved antimycobacterial properties of hit molecules.

Computer-aided identification of lead compounds as Staphylococcal epidermidis FtsZ inhibitors using molecular docking, virtual screening, DFT analysis, and molecular dynamic simulation.

In an effort to face the multiple drug-resistant bacteria, various approaches have been discovered to design potent compounds and search new targets through computational design tools. With an aim to identify selective inhibitors against filamentous temperature-sensitive mutant Z (FtsZ), a library of Phase database compounds have been virtually screened. High-throughput virtual screening of compounds against Staphylococcal epidermidis FtsZ protein (4M8I) was performed using three sequential docking modes like high-throughput virtual screening, Glide standard precision, followed by Glide extra precision. Four top-ranked compounds were selected from molecular mechanics-generalized Born surface area (MM-GBSA) binding energy with better predicted free binding energies of - 89.309, - 54.382, - 53.667, and - 52.133 kcal/mol, respectively. It is also showed that the contribution of van der Waals and electrostatic solvation energy terms are playing a major part to make the hit molecule (T6288784) binding to S. epidermidis FtsZ protein. The result of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) and energy gap analysis predicts the molecular reactivity and stability of hit molecules. Subsequently, Lipinski's rule of five and properties of absorption, distribution, metabolism, and excretion (ADME) were to calculate their bioavailability. The average binding energy - 9.67 kcal/mol of the best proposed hit molecule (T6288784) was found with half-maximal inhibitory concentration (IC50) value to be 75.53 nM. A 15-ns molecular dynamics simulation study revealed the stable conformation of hit molecule. On a wide-range research discipline, in silico studies of our proposed compound confirm promising results and can be successfully used towards the development of novel FtsZ inhibitor with better binding affinity. Graphical Abstract.

Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors.

FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 µM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (R2 = .8319), cross validated coefficient (Q2 = .6213) and a high Fisher ratio (F = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (R2 = .83) and test set (R2 = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD-ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.

Keratomycosis caused by Blastoschizomyces capitatus.

Keratomycosis or fungal infections of cornea are common causes of ocular morbidity particularly in developing countries and in tropical climate. Traumatic inoculation is the predominant predisposing factor for this condition. Most of the cases are caused by filamentous fungi. Blastoschizomyces capitatus is one of the emerging fungal agents causing infection in different organ systems particularly in immunocompromised individuals. Barring one case of keratitis and melting of corneal graft there is no report of keratomycosis by B. capitatus. Here we present a case of keratomycosis caused by B. capitatus, which is the first such case reported from India.

A comprehensive study on regulatory requirements for development and filing of generic drugs globally.

The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for the companies to develop a single drug which can be simultaneously submitted in all the countries for approval. The regulatory strategy for product development is essentially to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. It not only includes the process of regulating and monitoring the drugs but also the process of manufacturing, distribution, and promotion of it. One of the primary challenges for regulatory authority is to ensure that the pharmaceutical products are developed as per the regulatory requirement of that country. This process involves the assessment of critical parameters during product development.