Design, synthesis and biological evaluation of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors.

A series of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives has been designed, synthesized and screened for their in vitro human carbonic anhydrase (hCA; EC 4.2.1.1) inhibition potential. These newly synthesized sulfonamide compounds were assessed against isoforms hCA I, II, VII and XII, with acetazolamide (AAZ) as a reference compound. The majority of these compounds were found quite weak inhibitor against all tested isoforms. Compound 15 showed a modest inhibition potency against hCA I (Ki = 73.7 μM) and hCA VII (Ki = 85.8 μM). Compounds 19 and 25 exhibited hCA II inhibition with Ki values of 96.0 μM and 87.8 μM, respectively. The results of the present study suggest that, although the synthesized derivatives have weak inhibitory potential towards all investigated isoforms, some of them may serve as lead molecules for the further development of selective inhibitors incorporating secondary sulfonamide functionalities, a class of inhibitors for which the inhibition mechanism is poorly understood

A Multi-Country, Single-Blinded, Phase 2 Study to Evaluate a Point-of-Need System for Rapid Detection of Leishmaniasis and Its Implementation in Endemic Settings

With the advancement of isothermal nucleic acid amplification techniques, detection of the pathogenic DNA in clinical samples at point-of-need is no longer a dream. The newly developed recombinase polymerase amplification (RPA) assay incorporated in a suitcase laboratory has shown promising diagnostic efficacy over real-time PCR in detection of leishmania DNA from clinical samples. For broader application of this point-of-need system, we undertook a current multi-country diagnostic evaluation study towards establishing this technique in different endemic settings which would be beneficial for the ongoing elimination programs for leishmaniasis. For this study purpose, clinical samples from confirmed visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) patients were subjected to both real-time PCR and RPA assay in Bangladesh, India, and Nepal. Further skin samples from confirmed cutaneous leishmaniasis (CL) patients were also included from Sri Lanka. A total of 450 clinical samples from VL patients, 429 from PKDL patients, 47 from CL patients, and 322 from endemic healthy/healthy controls were under investigation to determine the diagnostic efficacy of RPA assay in comparison to real-time PCR. A comparative sensitivity of both methods was found where real-time PCR and RPA assay showed 96.86% (95% CI: 94.45–98.42) and 88.85% (95% CI: 85.08–91.96) sensitivity respectively in the diagnosis of VL cases. This new isothermal method also exhibited promising diagnostic sensitivity (93.50%) for PKDL cases, when a skin sample was used. Due to variation in the sequence of target amplicons, RPA assay showed comparatively lower sensitivity (55.32%) than that of real-time PCR in Sri Lanka for the diagnosis of CL cases. Except for India, the assay presented absolute specificity in the rest of the sites. Excellent concordance between the two molecular methods towards detection of leishmania DNA in clinical samples substantiates the application of RPA assay incorporated in a suitcase laboratory for point-of-need diagnosis of VL and PKDL in low resource endemic settings. However, further improvisation of the method is necessary for diagnosis of CL

Virtual Screening and Free Energy Estimation for Identifying Mycobacterium Tuberculosis Flavoenzyme DprE1 Inhibitors

we investigated the promising MTB drug target protein, DprE1 (decaprenylphosphoryl-β-d-ribose 2’-epimerase), involve in cell was synthesis of Mycobacterium tuberculosis and plays a crucial role in host pathogenesis, virulence, lethality and survival under stress. Considering the emergence of different variants of drug resistant MTB are one of the major threats worldwide which essentially requires more effective new drug molecules with no major side effects. Here, we employed comprehensive computational methods for the structure based virtual screening of bioactive anti-tuberculosis compounds from chemical libraries ChEMBL, characterized the physicochemical properties analyses and the trajectories obtained from MD simulations were used for estimation of binding free energy, applying molecular theory of solvation (MM/PBSA, MM/GBSA AND MM/3DRISM-KH). All results were compared with known DprE1 inhibitors. Our studies suggest that four compounds (ChEMBL2441313, ChEMBL2338605, ChEMBL441373 and ChEMBL1607606) compounds may be explored as lead molecules for the rational drug designing of DprE1-inhibitors in MTB therapy.<br /

To find the awareness about glaucoma and the level of knowledge and the various reasons for the lack of its knowledge in patients coming to Ophthalmology Out Patient Department in Tertiary Care Centre in South Bihar

Abstract Introduction: Glaucoma blindness imposes significant economic burden not only for individuals affected but also it increases healthcare cost, impairs quality of life, increases rehabilitation cost for the blind which all affects the economic growth of a nation. It also results a huge burden for the healthcare system and government’s spending toward health care. Aim and Objective: To find the awareness about glaucoma and the level of knowledge and the various reasons for the lack of its knowledge in patients coming to Ophthalmology Out Patient Department in Tertiary Care Centre in South Bihar Material and Methods: A population-based study, was conducted in the outpatient department of a tertiary medical centre between Oct 2019 and July 2020. All the patients above 20 years of age attending the OPD were chosen randomly and asked “if they have heard about glaucoma” in their local language (Hindi). If yes, a subsequent question was asked to them. The patients who were undergoing treatment for glaucoma were excluded from the study. Results :Out of 800 study subjects only Thirty five (4.4%) participants were aware of the term glaucoma. 17( 48.57%) out of 35 knows that risk of glaucoma increases with age, 8(22.86%) says glaucoma not increases with age, rest10( 28.57%) don’t know the answer. On asking if anyone can have glaucoma, 18 says yes, 9 says No, and rest 8 don’t know. Out of 35, 16(45.71%) knows that glaucoma is preventable, 5( 14.29%) know it wrong, 14 (40%) don’t know. On asking whether treatment of glaucoma possible 13(37.14%) says yes, 11(31.43%) says no, 11 (31.43%) say don’t know. 20 out of 35 study subjects says Vision affected in early age in glaucoma Conclusion: Awareness and knowledge of glaucoma is low among our study subjects. Most common source of information was TV/Radio/Newspaper. An efficient Information, Education and Communication (IEC) strategy needed to improve knowledge and awareness. Keywords: IEC, Tertiary Care Centre, Glaucoma

Knowledge, attitude, practices towards covid-19 profile of patients attending outpatient department of ophthalmology in a tertiary care hospital in south Bihar - a cross – sectional survey

Introduction: Ophthalmology as a speciality is at an increased risk as most of the procedures bring ophthalmologists in close contact with the patient’s eyes and face. Various parts of the patient’s face touch the ophthalmic equipment, thus increasing the risk of spread of infection through aerosolized particles from respiratory droplet and contact. There are also reports of SARS- CoV-2 identified in tears and conjunctival swabs, thus putting ophthalmologists at the risk. Aim and Objectives: To know the KAP (Knowledge, Attitude and Practices) towards COVID-19 and profile of patients and the various reasons for the lack of its knowledge in patients coming to Ophthalmology Out Patient Department in Tertiary Care Centre in South Bihar. Methodology : This is Cross- Sectional Study conducted&nbsp; from May 2020 to Sept 2020, After getting approval by Institutional Ethics Committee, data on demographics and awareness of COVID-19 were collected through face to face interview using pretested semi- structured questionnaire in the vernacular language, which is Hindi. Result : Very few respondent was aware about eye involvement in COVID 19 infection.78% respondent don’t know about eye involvement in COVID-19 cases, 12 % say discharge is the most common symptoms of eye involvement in COVID cases. 7% say pain is the main symptoms, 3% say that redness in eye is important feature of COVID-19 infection.59% of the respondent believes that hand should be washed before touching face, otherwise infection can spread. Majority of study subjects (63%) believes that COVID-19 infection occurs mostly in old people, 23% say children is affected more, 11% don’t know exactly whereas only 3% believes that COVID-19 infection occurs most commonly in adults Conclusion: The findings suggest that study subjects who participated in this study have satisfactory level of knowledge on COVID-19, but compliance with the necessary guideline by the government, which are necessary for mitigating the spread of COVID-19 is not good. Internet and media play an important role in acquiring needed knowledge

Insights into the DNA binding induced thermal stabilization of transcription factor FOXP3

<p>The transcription factor FOXP3 is required for the development and function of regulatory T cells. Here, we studied the dynamics of FOXP3 in the presence and absence of DNA target sequence. Multiple molecular dynamics (MD) simulations were employed to investigate the role of DNA in enhancing the stability of FOXP3 via protein–DNA interactions, and to study the structural transition in protein at three different temperatures (300, 350, and 400 K). Results indicate that FOXP3 is stabilized by DNA even though the temperature rises up to 400 K. FOXP3 is found to undergo significant conformational change at a higher temperature, however, DNA provides greater rigidity and lower overall conformational flexibility, resulting in the global stabilization of FOXP3. The conformational restriction of FOXP3-DNA complex is probed with essential dynamics (ED). Free-energy landscape analysis at high temperature shows the presence of metastable intermediates, suggesting the reason behind the observed thermal stability. Secondary structural snapshots clearly indicate the presence of non-native interactions between DNA and protein. This study increases our understanding of the dynamic behaviors and the interaction mechanism of FOXP proteins and DNA at the atomic level and offers a model for studying the structural biology of transcriptional regulation.</p> <p>Communicated by Ramaswamy H. Sarma</p

Effect of Double Mutation (L452R and E484Q) on the Binding Affinity of Monoclonal Antibodies (mAbs) against the RBD—A Target for Vaccine Development

The COVID-19 pandemic, caused by SARS-CoV-2, emerges as a global health problem, as the viral genome is evolving rapidly to form several variants. Advancement and progress in the development of effective vaccines and neutralizing monoclonal antibodies are promising to combat viral infections. In the current scenario, several lineages containing “co-mutations” in the receptor-binding domain (RBD) region of the spike (S) protein are imposing new challenges. Co-occurrence of some co-mutations includes delta (L452R/T478K), kappa (L452R/E484Q), and a common mutation in both beta and gamma variants (E484K/N501Y). The effect of co-mutants (L452R/E484Q) on human angiotensin-converting enzyme 2 (hACE2) binding has already been elucidated. Here, for the first time, we investigated the role of these RBD co-mutations (L452R/E484Q) on the binding affinity of mAbs by adopting molecular dynamics (MD) simulation and free-energy binding estimation. The results obtained from our study suggest that the structural and dynamic changes introduced by these co-mutations reduce the binding affinity of the viral S protein to monoclonal antibodies (mAbs). The structural changes imposed by L452R create a charged patch near the interfacial surface that alters the affinity towards mAbs. In E484Q mutation, polar negatively charged E484 helps in the formation of electrostatic interaction, while the neutrally charged Q residue affects the interaction by forming repulsive forces. MD simulations along with molecular mechanics-generalized Born surface area (MMGBSA) studies revealed that the REGN 10933, BD-368-2, and S2M11 complexes have reduced binding affinity towards the double-mutant RBD. This indicates that their mutant (MT) structures have a stronger ability to escape from most antibodies than the wild type (WT). However, EY6A Ab showed higher affinity towards the double MT-RBD complex as compared to the WT. However, no significant effect of the per-residue contribution of double-mutated residues was observed, as this mAb does not interact with the region harboring L452 and E484 residues

Development of inorganic-organic hybrid nanostructured material for H2O2 sensing application

An organic-inorganic hybrid nanoparticle (HNPs) composed of Sm(TTA) _3 Phen, a coordination compound, and NaY _0.78 Er _0.02 Yb _0.20 F _4, an upconversion nanoparticles (UCNPs), has been developed and used for H _2 O _2 sensing application. Herein, Sm(TTA) _3 Phen absorbs ultraviolet (UV) light and gives fluorescence in yellow-red-near infrared (NIR) region. Whereas, the UCNPs absorb NIR radiations (980 nm) and consequently emit in green-red region through photon upconversion process. Two important optical phenomena are observed when HNPs are simultaneously excited with UV (266 nm) and NIR (980 nm) laser radiation- (i) an energy transfer from Sm ^3+ to Er ^3+ ions, and (ii) color tunable emission from red to green, if the power of 980 nm laser is varied. Further, the material is highly competent to sense H _2 O _2 through fluorescence quenching of Sm ^3+ emission in presence of H _2 O _2 . The nature of quenching is conspicuously different for different concentration/volume range of H _2 O _2 . For lower volume range, the rate of decrease of emission/excitation intensity is linear, while for higher volume range the decay in intensity is exponential. The attained minimum detection limit for H _2 O _2 is 2 μ l, which is significant for sensing applications

Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types