DESIGN, IN-SILICO DOCKING AND PREDICTIVE ADME PROPERTIES OF NOVEL PYRAZOLINE DERIVATIVES WITH SELECTIVE HUMAN MAO INHIBITORY ACTIVITY

Objectives: Curcumin, a known hMAO-A (human Monoamine oxidase-A) inhibitor from Curcuma longa has never been recognized for this property due to its poor permeability and extensive metabolism. Thus, the main objective of this study is to incorporate structural features of Curcumin in the pyrazoline scaffold as an attempt to get potent, selective hMAO-isoform inhibitors with improved permeability.Methods: A series of twelve novel 4, 4'-(4, 5-dihydro-1H-pyrazole-3,5-diyl)bis(2-methoxyphenol) derivatives (1-12) were designed based on the structure of Curcumin. All the designed compounds were evaluated for their hMAO inhibitory activity by in-silico docking studies (Autodock4.20). The both isomers (R-and S-isomer) are considered for simulation approach to understand the effect of chirality and other structural features that determine the potency and selectivity. In order to judge the pharmacokinetic behavior, all the derivatives were evaluated for their in-silico ADME properties by using Qik Prop v 3.0.Results: The results of the present study showed that all the designed compounds were found to be potent and selective hMAO-isoform inhibitors, and exhibited lead like properties from the calculated ADME parameters. Curcumin was taken as a standard for comparison to judge any improvement in permeability.Conclusion: The design strategy adopted has predicted improved potency, selective towards hMAO-isoform and permeability characteristics in comparison with Curcumin.Â

DIFFERENT ANALYTICAL TECHNIQUES FOR THE ANALYSIS OF ANTICANCER DRUGS-BOSUTINIB, ENCORAFENIB AND DABRAFENIB-A REVIEW

In this present situation there is an increase in the number of diseases has been observed but before this drug come to market, it must undergo several procedures. The validation and analytical methods are the important techniques that help in ensuring its purity and reliability. This process involves the use of various analytical techniques to collect data about the drug. This review includes various types of analytical techniques such as ultraviolet-visible Spectrophotometric and chromatography methods such as high-performance liquid chromatography, hyphenation techniques such as LC-MS for the estimation of selected anti-cancer drugs

Correlation of Interleukin-17 and 23 Inflammatory Markers with Genetically Transmitted Spondyloarthritis Patients at a Tertiary Care Facility, South India

Human leukocyte antigens (HLA) are genetically derived proteins in the major histocompatibility complex. They help distinguish “self” and “non-self” antigens and are essential in interacting with the immune cells inside the body. The present research work examines the prevalence of HLA-B27 among patients suspected of Spondyloarthritis (SpA), which has also been correlated with Interleukin-17/23 Inflammatory Markers and other clinical manifestations and was carried out between August 2017 to January 2021. The patient’s blood samples were collected and tested for HLA-B27 and Interleukin-17/23 inflammatory markers. Among 289 SpA patients, 60% (172) were males, and 40% (117) were females, with a ratio of 1.5:1. Ankylosing Spondylitis (65.1%) was found to be the most prevalent subgroup of SpA among the patients, closely followed by reactive arthritis (21%), psoriatic arthritis (10.7%), undifferentiated spondyloarthritis (2.1%), and inflammatory bowel disease with associated arthritis (1%). HLA-B27 was found to be positive in 54% (156) out of 289 patients. Normal IL-17 ranges were seen in 42% of HLA-B27- positive patients, while increased IL-17 was seen in 58% of the population with positive HLA-B27 cases. IL-23 was found within normal ranges in 40% of positive HLA-B27 cases, while it was found to be increased in 60% of the positive HLA-B27 positive subjects. We concluded that HLA-B27 was found to be positive among more than half of the patient population with SpA. The early detection of HLA-B27 may aid in changing lifestyle to prevent Spondyloarthritides

Therapeutic and Diagnostic Approaches by using Nanotechnology in SARS-CoV-2 Infections

Severe Acute Respiratory Syndrome Corona Virus-2 infection is a universal threat in recent days, hence early diagnosis and treatment play a pivotal role in controlling the spread thereby preventing them to become endemic. A newer promising approach by Nanotechnology plays an essential role in targeting the specific pathogens for therapeutic and diagnosis of Viral infection. Certain Nano platforms like Microneedle array delivered Virus S1 subunit vaccines, spike protein nanoparticles, Lumazine synthase Nanoparticles, Silver Nanoparticles, Self-Assembling Protein Nanoparticles against Viral therapy are the upcoming applications as a therapeutic approach. Nucleic acid amplification techniques and Surface-enhanced Raman Spectroscopy shows a high specificity with the immunoassay strategy. In recent days, Colloidal Gold – Nanoparticles and silicon nanoparticles have been widely used as a point of care for quick detection of IgG and IgM antibodies obtained from the virus as a diagnostic approach. Additionally, the Nanoparticles serve as a significant improvement in Personal Protective Equipment and protect against exposure to the virus. As a result of repurposing as well as for the development of the drug, apparently, Nanoparticles themselves and their concomitant therapy or their carriers will be advantageous in making a therapeutic and diagnostic approach against Severe Acute Respiratory Syndrome Corona Virus-2 infections

A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses

Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are capsid binders that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.Peer reviewe

DESIGN, IN-SILICO DOCKING AND PREDICTIVE ADME PROPERTIES OF SOME THIAZOLIDINE-2, 4-DIONES DERIVATIVES AS PPARγ MODULATORS

Objectives: Thiazolidinediones a promising and privileged scaffold in medicinal chemistry that has been popularly recognized for its antidiabetic activity. The objective of the current study is to explore the effects of substitution replacing the acidic hydrogen of thiazolidinedione ring.Methods: The protocol adopted was (i) In silico enumeration of small chemical library, (ii) molecular docking simulation and (iii) selection of hits based on predicted ADME/TOX properties to support further synthetic enumeration of chemical compounds for biological evaluation.Results: The results of the present study showed that all the designed compounds were found to be potent PPARγ modulators and shows promising lead like properties from the calculated ADME/TOX parameters. Rosiglitazone was taken as a standard for the comparison of In silico studies.Conclusion: The design strategy adopted has predicted improved potency, less toxicity and a better binding mode prediction towards PPARγ.Keywords: PPARγ, Pharmacokinetic parameters, Schrodinger, Structure-activity relationship, Molecular docking simulation, Pharmacokinetic parameter

Designing and In Silico Evaluation of Some Non-Nucleoside <i>MbtA</i> Inhibitors: On Track to Tackle Tuberculosis

The WHO database shows that mycobacterium tuberculosis has become an epidemic worldwide due to its pathogenicity and virulence, which have magnified its infectiousness. The situation becomes grimmer with the prevalence of MDR-TB, XDR-TB, emergence of cross-resistance, ineffectiveness of novel therapeutic targets, failure of novel medications in clinical trials, currently available drugs losing their therapeutic efficacy, lack of drug discovery efforts due to poor ROI, and the existence of co-infections; i.e., HIV, TB, COVID, and HIV-TB-COVID. Following our prior studies described by Stirret et al. in 2008, Ferreras et al. in 2011, and Shyam et al. in 2021, herein we focus on exploring pyrazoline-based mycobactin analogs (non-specific mycobactin biosynthesis inhibitors) targeting the MbtA enzyme (first step of mycobactin biosynthesis) with a hope of finding a more potent analog showing a high affinity for MbtA. The design strategy involves retaining the structural features of mycobacterial siderophores. Herein, a small library (12 molecules) of mycobactin analogs were designed, keeping the necessary skeleton (diaryl-substituted pyrazoline (DAP)) intact and assessed their stability using in silico tools. In order to determine the binding modes and inhibitory profiles of the designed ligands, docking was carried out in the active pocket of MbtA (analogous with the homologous structure with PDB ID: 1MDB). The best energy conformation (lowest score) of each docked ligand was represented graphically. The ADMET profile of each molecule was analyzed. The best molecule that revealed a good ADMET profile was taken up for MD simulation study (45 ns). Results revealed that the designed compounds GV08 (−8.80 kcal/mol, 352.58 nM), GV09 (−8.61 kcal/mol, 499.91 nM), GV03 (−8.59 kcal/mol, 508.51 nM), and GV07 (−8.54 kcal/mol, 553.44 nM) had a good docking score and inhibition constant. Of these, GV08 showed a good ADME profile with all the major parameters lying in the acceptable ranges. They also showed the least toxicity with no hepatotoxicity and skin sensitization. MD simulation studies of GV08 also suggest that it was stable throughout the course of simulation. This could be justified by RMSD, RMSF, and H-bond plots. The future scope invalidates these findings through synthesis, characterization, and intracellular activity

Design, Development, and In Silico Study of Pyrazoline-Based Mycobactin Analogs as Anti-Tubercular Agents

The pathogenicity and virulence of Mycobacterium tuberculosis has further potentiated its infectiousness, making it a killer disease, as is evident from the WHO database. Eradicating the TB epidemic by 2030 is amongst the major health targets of the United Nations Sustainable Development Goals (SDGs). The increase in multidrug-resistant TB (MDR-TB) cases has challenged and prompted the scientific community to develop novel chemotherapeutic agents with novel mechanisms of action. The goal can be achieved by &ldquo;conditionally essential target&rdquo; (CET)-based drug design. The research pertaining to the mycobactin biosynthesis pathway (MBP) relating to iron acquisition is in a nascent stage; the pathway serves as a promising endogenous target for novel lead compound discoveries (non-specific MBP inhibitors). As a continuation of our previous research, reported by Stirret et al., 2008 and Ferreras et al., 2011, in this study we further aim to explore the structural diversity of the previously identified active molecules as this could lead to the discovery of a more potent analog. Eventually, we designed a small library of mycobactin analogs retaining diaryl-substituted pyrazoline (DAP) as the basic scaffold and tested their in silico stabilities by molecular docking (AutoDock 4.2.6). Docking of the designed molecules was performed in the active site of the MbtA receptor (by analogy with the related structure, PDB: 1MDB) to evaluate the binding modes and inhibitory profiles. The lowest energy conformation of each docked ligand was analyzed with the BIOVIA Discovery Studio Visualizer. The docking results identified GM08 and GM09 as potent inhibitors which could therefore serve as good leads. The ADMET profile also revealed satisfactory results. Furthermore, what remains to be seen is the stability of each molecule by employing MD simulation along with intracellular activity

N,N-Diethyl-2-[5-(4-methoxybenzylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetamide

In the title compound, C17H20N2O4S, the thiazolidine (r.m.s. deviation = 0.022 Å) and phenyl rings (major and minor occupancies) are inclined to one another by 6.3 (3) and 10.5 (3)°, respectively. The molecular conformation is stabilized by an intramolecular C—H...S interaction. In the crystal, molecules are linked by C—H...O hydrogen bonds, which generate R22(18), R22(24) and R21(7) ring motifs. Aromatic π–π stacking interactions are also observed