Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies.

We provide promising computational (in silico) data on phytochemicals (compounds 1-10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1-10 followed the Lipinski rules of five (RO5) and ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking of compounds 1-10 demonstrated their binding with the catalytic dyad (CYS145 and HIS41) of 3CLPro and catalytic triad (CYS111, HIS272, and ASP286) of PLPro. Moreover, the implementation of the covalent (irreversible) docking protocol revealed that only compounds 7, 8, and 9 possess covalent warheads, which allowed the formation of the covalent bond with the catalytic dyad (CYS145) in 3CLPro and the catalytic triad (CYS111) in PLPro. Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analysis from molecular dynamic (MD) simulations revealed that complexation between ligands (compounds 7, 8, and 9) and 3CLPro and PLPro was stable, and there was less deviation of ligands. Overall, the in silico data on the inherent properties of the above phytochemicals unravel the fact that they can act as reversible inhibitors for 3CLPro and PLPro. Moreover, compounds 7, 8, and 9 also showed their novel properties to inhibit dual targets by irreversible inhibition, indicating their effectiveness for possibly developing future drugs against SARS-CoV-2. Nonetheless, to confirm the theoretical findings here, the effectiveness of the above compounds as inhibitors of 3CLPro and PLPro warrants future investigations using suitable in vitro and in vivo tests.

Structural basis for the mutation-induced dysfunction of the human IL-15/IL-15α receptor complex.

In silico strategies offer a reliable, fast, and inexpensive, way compared to the clumsy in vitro approaches to boost understanding of the effect of amino acid substitution on the structure and consequently the associated function of proteins. In the present work, we report an atomistic-based, reliable in silico structural and energetic framework of the interactions between the receptor-binding domain of the Interleukin-15 (IL-15) protein and its receptor Interleukin-15α (IL-15α), consequently, providing qualitative and quantitative details of the key molecular determinants in ligand/receptor recognition. Molecular dynamics simulations were used to investigate the dynamic behavior of the specific binding between IL-15 and IL-15α followed by estimation of the free energies via molecular mechanics/generalized Born surface area (MM/GBSA). In particular, residues Y26, E46, E53, and E89 of the IL-15 protein receptor-binding domain are identified as main hot spots, shaping and governing the stability of the assembly. These results can be used for the development of neutralizing antibodies and the effective structure-based design of protein-protein interaction inhibitors against the so-called orphan disease, vitiligo.

Compounds Related to Saudin and Three New Series of Diterpenoids from Clutia lanceolata.

Clutia lanceolata is a medicinal plant native to Ethiopia and sub-Saharan Africa and to the Arabian Peninsula. It is used traditionally in Saudi Arabia for the treatment of diabetes. Previous phytochemical analysis of this species has been limited to the identification of methylthiocoumarins. Further work has led to isolation of 19 new diterpenoids in three structural classes. Their structures were established by HRMS and by a range of NMR techniques (1H, 13C, COSY, NOESY, HSQC, HMBC), with confirmation for some examples by X-ray crystallography. NOESY and 1H-1H NMR coupling constants gave the relative stereochemical configurations and conformational information, with absolute configurations being established through X-ray crystallography. One example closely related to the known hypoglycemic compound saudin (found in C. richardiana and also in C. lanceolata) and one with a different core tetracycle were found to enhance strongly the glucose-triggered release of insulin from murine pancreatic islets. Biosynthetic proposals for the three groups of new diterpenoids by alternative cyclization of a common precursor are put forward. Lanceolide P (16) is proposed as a lead compound for further development for the treatment of diabetes.

Identification of potent anti-immunogenic agents through virtual screening, 3D-QSAR studies, and in vitro experiments.

A wealth of literature has highlighted the discovery of various immune modulators, frequently used in clinical practice, yet associated with numerous drawbacks. In light of this pharmacological deficiency, medical scientists are motivated to develop new immune modulators with minimized adverse effects yet retaining the improved therapeutic potential. T-cell differentiation and growth are central to human defense and are regulated by interleukin-2 (IL-2), an immune-modulatory cytokine. However, scientific investigation is hindered due to its flat binding site and widespread hotspot residues. In this regard, a prompt and logical investigation guided by integrated computational techniques was undertaken to unravel new and potential leads against IL-2. In particular, the combination of score-based and pharmacophore-based virtual screening approaches were employed, reducing the data from millions of small molecules to a manageable number. Subsequent docking and 3D-QSAR prediction via CoMFA further helped remove false positives from the data. The reliability of the model was assessed via standard metrics, which explain the model's fitness and the robustness of the model in predicting the activity of new compounds. The extensive virtual screening herein led to the identification of a total of 24 leads with potential anti-IL-2 activity. Furthermore, the theoretical findings were corroborated with in vitro testing, further endorsing the anti-inflammatory potential of the identified leads.

Marine Natural Compound (Neviotin A) Displays Anticancer Efficacy by Triggering Transcriptomic Alterations and Cell Death in MCF-7 Cells.

We investigated the anticancer mechanism of a chloroform extract of marine sponge (Haliclona fascigera) (sample C) in human breast adenocarcinoma (MCF-7) cells. Viability analysis using MTT and neutral red uptake (NRU) assays showed that sample C exposure decreased the proliferation of cells. Flow cytometric data exhibited reactive oxygen species (ROS), nitric oxide (NO), dysfunction of mitochondrial potential, and apoptosis in sample C-treated MCF-7 cells. A qPCR array of sample C-treated MCF-7 cells showed crosstalk between different pathways of apoptosis, especially BIRC5, BCL2L2, and TNFRSF1A genes. Immunofluorescence analysis affirmed the localization of p53, bax, bcl2, MAPKPK2, PARP-1, and caspase-3 proteins in exposed cells. Bioassay-guided fractionation of sample C revealed Neviotin A as the most active compound triggering maximum cell death in MCF-7, indicating its pharmacological potency for the development of a drug for the treatment of human breast cancer.

Probing CAS database as prospective antiviral agents against SARS-CoV-2 main protease.

The pandemic of COVID-19 has an unprecedented impact on global health and economy. The novel SARS-CoV-2 is recognized as the etiological agent of current outbreak. Because of its contagious human-to-human transmission, it is an utmost global health emergency at present. To mitigate this threat many scientists and researchers are racing to develop antiviral therapy against the virus. Unfortunately, to date no vaccine or antiviral therapeutic is approved thus there is an urgent need to discover antiviral agent to help the individual who are at high risk. Virus main protease or chymotrypsin-like protease plays a pivotal role in virus replication and transcription; thus, it is considered as an attractive drug target to combat the COVID-19. In this study, multistep structure based virtual screening of CAS antiviral database is performed for the identification of potent and effective small molecule inhibitors against chymotrypsin-like protease of SARS-CoV-2. Consensus scoring strategy combine with flexible docking is used to extract potential hits. As a result of extensive virtual screening, 4 hits were shortlisted for MD simulation to study their stability and dynamic behavior. Insight binding modes demonstrated that the selected hits stabilized inside the binding pocket of the target protein and exhibit complementarity with the active site residues. Our study provides compounds for further in vitro and in vivo studies against SARS-CoV-2.

Oncoglabrinol C, a new flavan from Oncocalyx glabratus protects endothelial cells against oxidative stress and apoptosis, and modulates hepatic CYP3A4 activity.

Active herbal or natural compounds have high chemical diversity and specificity than synthetic drugs. Recently, we have validated the hypoglycemic salutation of Oncocalyx glabratus in rodent model, and demonstrated the activation of PPARα/γ by its newly ioslated flavan derivative Oncoglabrinol C (5,3'-Dihydroxyflavan 7-4'-O-digallate) in liver cells (HepG2). Here we evaluated the potential of Oncoglabrinol C against Dichlorofluorescin (DCFH) and Methylglyoxal (MGO) induced endothelial cells (HUVEC) oxidative and apoptotic damage, including activation of PXR-mediated hepatic CYP3A4. Our MTT assay showed protection of ~57% and ~63.5% HUVEC cells by 10 and 20 µg/ml doses of Oncoglabrinol C, respectively through attenuating DCFH triggered free-radicals. Also, the two doses effectively protected ~53% and ~65.5% cells, respectively by reversing MGO toxicity. In DCFH and MGO treated cells, Oncoglabrinol C (20 µg/ml) effectively downregulated caspase 3/7 activity by ~33% and ~43.5%, respectively. Moreover, in reporter gene (dual-luciferase) assay, Oncoglabrinol C (20 µg/ml) moderately activated hepatic CYP3A4. Molecular docking of Oncoglabrinol C indicated its strong interactions with cellular caspase 3/7, PPARα/γ and PXR proteins, which supported its anti-apoptotic (antagonistic) as well as pro-hypoglycemic and PXR/CYP activating (agonistic) activities. Taken together, our findings demonstrated the potential of Oncoglabrinol C in reversing the endothelial oxidative and apoptotic damage as well as in the activation of hepatic CYP3A4. This warrants further evaluations of Oncoglabrinol C and related compounds towards developing effective and safe drugs against diabetes associated cardiovascular disorders.

New flavonoids from the Saudi Arabian plant Retama raetam which stimulates secretion of insulin and inhibits α-glucosidase.

Retama raetam is a bush which is a member of the family Fabaceae. It is used traditionally in North Africa and Saudi Arabia for the treatment of diabetes. Several flavonoids and alkaloids are already known from this plant. Chromatographic fractionation and purification led to the isolation of three new derivatives of prenylated flavones, retamasin C-E, and four new derivatives of prenylated isoflavones, retamasin F-I, in addition to two isoflavones which have not been previously reported in this plant. Particularly interesting structures included isoflavones containing 3,5-dihydro-2H-2,5-methanobenzo[e][1,4]dioxepine and 3a,8b-dihydro-7-hydroxyfuro[3,2-b]benzo[2,1-d]furan units, both of which are new amongst natural product flavonoids. Five new examples (two flavones and three isoflavones) strongly enhanced the glucose-triggered release of insulin by murine pancreatic islets and one isoflavone was a potent inhibitor of α-glucosidase. This study may rationalise the traditional medicinal use of R. raetam and provide new leads for drug design in the treatment of diabetes.

Antidiabetic, antioxidant, molecular docking and HPTLC analysis of miquelianin isolated from Euphorbia schimperi C. Presl.

The present study demonstrates the miquelianin or quercetin 3-O-glucuronide (compound 1) isolated from aerial parts of Euphorbia schimperi exhibited significant results for antioxidant and antidiabetic potential. The compound 1 along with kaempferol 3-O-glucuronide (compound 2) and quercetin 3-O-rhamnoside (compound 3) isolated from the same source were quantified by validated HPTLC method. Antioxidant activity was determined by chemical means in terms of ABTS radical cation and DPPH radical scavenging activity. Compound 1 showed significant scavenging activity in both ABTS and DPPH assays as compared to standard BHA. In ABTS method IC50 values of compound 1 and standard BHA is found to be 58.90 ±â€¯3.40 µg/mL and 28.70 ±â€¯5.20 µg/mL respectively while in DPPH assay IC50 values of Compound 1 and standard BHA is 47.20 ±â€¯4.90 µg/mL and 34.50 ±â€¯6.20 µg/mL respectively. Antidiabetic effect was studied through α-amylase and α-glucosidase inhibitory activity. The mechanistic approach through molecular modelling also support the strong binding sites of compound 1 which showed significant α-amylase and α-glucosidase inhibitory activities with IC50 values 128.34 ±â€¯12.30 and 89.20 ±â€¯9.20 µg/mL respectively as compared to acarbose 64.20 ±â€¯5.60 and 52.40 ±â€¯4.60 µg/mL respectively. The results of validated RP-HPTLC analyses revealed the concentration of compound 1 found to be 16.39 µg/mg and for compound 2 and compound 3 as 3.92 and 14.98 µg/mg of dried extract, respectively.

Neoclerodane Diterpenoids from Reehal Fatima, Teucrium yemense.

Teucrium yemense (Defl), locally known as Reehal Fatima, is a medicinal plant commonly grown in Saudi Arabia and Yemen. Phytochemical investigation of the aerial parts of T. yemense yielded six new neoclerodane diterpenoids, namely fatimanol A-E (1, 2, 3, 5, and 6) and fatimanone (4), and the known teulepicephin (7). As both the Teucrium genus and the related Lamiaceae family have previously been widely reported to possess anthelmintic and antimicrobial activities, the structural and biological characterization of the seven diterpenoids was pursued. The structures of the new compounds were elucidated from their 2D NMR and MS profiles and by comparison to related compounds. The structure of fatimanol D (5) was confirmed by X-ray crystallographic analysis. The new structures contribute to the breadth of knowledge of secondary metabolites in this genus.

Two New Sesquiterpene Alcohols Isolated from Senecio hadiensis Forssk. Grown in Saudi Arabia.

Phytochemical investigation on the aerial parts of Senecio hadiensis Forssk. led to the isolation of two new sesquiterpenoids, presilphiperfolan-2α,5α,8α-triol (1) and presilphiperfolan-2α,5α,8α,10α-tetraol (2) featuring the rare presilphiperfolane-type frameworks. The structures of 1 and 2 were elucidated on the basis of extensive spectroscopic (1D- and 2D-NMR, HR-ESI-MS) methods and by comparison with the literature data. The isolates 1 and 2 were evaluated in-vitro for antiinflammatory, cytotoxic, and peroxisome proliferator activated receptor alpha and gamma (PPARα and PPARγ) agonistic activities.

Inter-species comparative antioxidant assay and HPTLC analysis of sakuranetin in the chloroform and ethanol extracts of aerial parts of Rhus retinorrhoea and Rhus tripartita.

CONTEXT: Extensive research on Rhus (Anacardiaceae) shows their antioxidant potential, which warrants further evaluation of its other species. OBJECTIVE: To perform a comparative antioxidant assay on extracts of R. retinorrhoea and R. tripartita, including sakuranetin quantification by a validated HPTLC method. MATERIALS AND METHODS: In vitro antioxidant assay was performed on chloroform and ethanol extracts of R. retinorrhoea Steud. ex Oliv. (RRCE and RREE) and R. tripartita (Ucria) Grande (RTCE and RTEE) by DPPH radical scavenging (at 31.25, 62.5, 125, 250 and 500 µg/mL concentrations) and ß-carotene-linoleic acid bleaching methods at 500 µg/mL concentration. Densitometric HPTLC method was developed and validated using toluene: ethyl acetate: methanol (8:2:0.2; v/v/v) as mobile phase, executed on glass-backed silica gel F254 plate and scanned at 292 nm. RESULTS: Antioxidant activity of Rhus extracts tested by the two methods (DPPH/BCB) was found in order of RTEE > RREE > RTCE > RRCE with IC50 118.67/256.26, 315.75/82.35, 827.92/380.0 and 443.69/292.75, respectively. Scanning of the HPTLC plate provided an intense peak of sakuranetin at Rf = 0.59. The estimated sakuranetin content in the dry weight of the extracts was highest in RREE (27.95 µg/mg) followed by RRCE (25.22 µg/mg), RTEE (0.487 µg/mg) and RTCE (0.0 µg/mg). Presence of sakuranetin in RREE, RRCE and RTEE supported the highest antioxidant property of the two Rhus species. Nonetheless, low sakuratenin in R. tripartita indicated the presence of other bioactive constituents responsible for synergistic antioxidant activity. CONCLUSION: The developed HPTLC method therefore guarantees its application in quality control of commercialized herbal drugs and formulations containing sakuranetin.

High-performance thin-layer chromatography based concurrent estimation of biomarkers ent-phyllanthidine and rutin in the dried aerial parts of Flueggea virosa.

The biomarkers are needed to be defined for standardization purposes so that safe and effective herbal formulations can be catered to the society. There is an urgent need for statistical support of herbal drugs because most of the herbal products are still used in the non-standardized form. This study is based on the development of a simple and sensitive RP-HPTLC method for concurrent estimation of two biomarkers ent-phyllanthidine and rutin in the methanol extract of aerial parts of Flueggea virosa. The developed method was found to be simple, economic and sensitive. Separation and quantification were performed with acetonitrile: water (4:6 V/V) used as the mobile phase on glass-backed RP-HPTLC plate. Detection of absorption maxima and quantification was done at 310 nm of UV region. The developed chromatographic system was found to give a sharp band for ent-phyllanthidine and rutin at Rf 0.73 ± 0.01 and 0.68 ± 0.01, respectively. The linearity ranges for ent-phyllanthidine, and rutin were found to be 200-1600 ngband-1 and 100-1400 ngband-1, respectively, with correlation coefficients (r2 values) of 0.998 and 0.997, respectively. The percentage of ent-phyllanthidine and rutin was found to be 9.121 ± 0.02% and 1.018 ± 0.04% (w/w), respectively. The resolution of bands and separation of constituents in FVME exhibited the perfect optimization of the developed method. The validation statistics supports the proposed method for standardizing crude drugs as well as formulations of a natural product containing ent-phyllanthidine and rutin.

Efficacy of preoperative single dose antibiotic in patients undergoing mesh repair for inguinal hernia.

BACKGROUND: Inguinal hernia is the commonest type of external hernias. Lichtenstein mesh repair is the most favoured technique of inguinal hernia repair nowadays. It is tension free repair of weakened inguinal wall using polypropylene mesh. The present study was conducted to determine the efficacy of single dose antibiotic with placebo on patients undergoing inguinal hernia mesh repair. METHODS: This randomised controlled trial was carried out in the Department of General Surgery, Ayub Teaching Hospital, Abbottabad from January to December 2011. The study population included male patients presenting with primary unilateral inguinal hernia, above 18 years of age. Mesh repair was performed in all patients. The patients were randomly divided into two groups. Patients in group A were given a single dose of antibiotic before inguinal hernia mesh repair and patients in group B were given placebo before inguinal hernia mesh repair. Efficacy of antibiotic and placebo was accessed in terms of surgical site infections (SSIs). RESULTS: A total of 166 cases of inguinal hernia mesh repair patients were recorded during the study period. A total of 83 patients were recruited in each group. Surgical site infection was found in 6 (7.2%) in Group B it was 15 (18.1%). The difference being statistically significant (p = 0.036). CONCLUSION: Antibiotic prophylaxis is a preferred option for mesh plasty.

Artificial Intelligence for Antimicrobial Resistance Prediction: Challenges and Opportunities towards Practical Implementation.

Antimicrobial resistance (AMR) is emerging as a potential threat to many lives worldwide. It is very important to understand and apply effective strategies to counter the impact of AMR and its mutation from a medical treatment point of view. The intersection of artificial intelligence (AI), especially deep learning/machine learning, has led to a new direction in antimicrobial identification. Furthermore, presently, the availability of huge amounts of data from multiple sources has made it more effective to use these artificial intelligence techniques to identify interesting insights into AMR genes such as new genes, mutations, drug identification, conditions favorable to spread, and so on. Therefore, this paper presents a review of state-of-the-art challenges and opportunities. These include interesting input features posing challenges in use, state-of-the-art deep-learning/machine-learning models for robustness and high accuracy, challenges, and prospects to apply these techniques for practical purposes. The paper concludes with the encouragement to apply AI to the AMR sector with the intention of practical diagnosis and treatment, since presently most studies are at early stages with minimal application in the practice of diagnosis and treatment of disease.

Novel anti­hepatitis B virus flavonoids sakuranetin and velutin from Rhus retinorrhoea.

Drug­resistance in hepatitis B virus (HBV), especially due to prolonged treatment with nucleoside analogs, such as lamivudine (LAM), remains a clinical challenge. Alternatively, several plant products and isolated phytochemicals have been used as promising anti­HBV therapeutics with no sign of resistance. Among all known Rhus species, R. coriaria, R. succedanea and R. tripartite have been widely studied for their anti­HBV efficacy, however, the effects of R. retinorrhoea have not been previously investigated. The current study reported the isolation of two flavonoids, namely sakuranetin (SEK) and velutin (VEL), from the dichloromethane fraction of R. retinorrhoea aerial parts using chromatography and spectral analyses. The two flavonoids (6.25­50 µg/ml) were pre­tested for non­hepatocytotoxicity using an MTT assay and their dose­ and time­dependent inhibitory activities against HBV [hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg)] in cultured HepG2.2.15 cells were assessed by ELISA. SEK and VEL at the selected doses (12.5 µg/ml) significantly inhibited HBsAg by ~58.8 and ~56.4%, respectively, and HBeAg by ~55.5 and ~52.4%, respectively, on day 5. The reference drugs LAM and quercetin (anti­HBV flavonoids), suppressed the production of HBsAg/HBeAg by ~86.4/~64 and ~84.5/~62%, respectively. Furthermore, molecular docking of the flavonoids with HBV polymerase and capsid proteins revealed the formation of stable complexes with good docking energies, thus supporting their structure­based antiviral mechanism. In conclusion, the present study was the first to demonstrate the anti­HBV therapeutic activities of SEK and VEL isolated from R. retinorrhoea.

Covalent Inhibitors from Saudi Medicinal Plants Target RNA-Dependent RNA Polymerase (RdRp) of SARS-CoV-2.

COVID-19, a disease caused by SARS-CoV-2, has caused a huge loss of human life, and the number of deaths is still continuing. Despite the lack of repurposed drugs and vaccines, the search for potential small molecules to inhibit SARS-CoV-2 is in demand. Hence, we relied on the drug-like characters of ten phytochemicals (compounds 1-10) that were previously isolated and purified by our research team from Saudi medicinal plants. We computationally evaluated the inhibition of RNA-dependent RNA polymerase (RdRp) by compounds 1-10. Non-covalent (reversible) docking of compounds 1-10 with RdRp led to the formation of a hydrogen bond with template primer nucleotides (A and U) and key amino acid residues (ASP623, LYS545, ARG555, ASN691, SER682, and ARG553) in its active pocket. Covalent (irreversible) docking revealed that compounds 7, 8, and 9 exhibited their irreversible nature of binding with CYS813, a crucial amino acid in the palm domain of RdRP. Molecular dynamic (MD) simulation analysis by RMSD, RMSF, and Rg parameters affirmed that RdRP complexes with compounds 7, 8, and 9 were stable and showed less deviation. Our data provide novel information on compounds 7, 8, and 9 that demonstrated their non-nucleoside and irreversible interaction capabilities to inhibit RdRp and shed new scaffolds as antivirals against SARS-CoV-2.

Exploring the Role of Antioxidants to Combat Oxidative Stress in Malaria Parasites.

BACKGROUND: Malaria, a global challenge, is a parasitic disease caused by Plasmodium species. Approximately 229 million cases of malaria were reported in 2019. Major incidences occur in various continents, including African and Eastern Mediterranean Continents and South-East Asia. INTRODUCTION: Despite the overall decline in global incidence from 2010 to 2018, the rate of decline has been almost constant since 2014. The morbidity and mortality have been accelerated due to reactive oxygen species (ROS) caused by oxidative stress generated by the parasite responsible for the destruction of host metabolism and cell nutrients. METHODS: The excessive release of free radicals is associated with the infection in the animal or human body by the parasites. This may be related to a reduction in nutrients required for the generation of antioxidants and the destruction of cells by parasite activity. Therefore, an intensive literature search has been carried out to find the natural antioxidants used to neutralize the free radicals generated during malarial infection. RESULTS: The natural antioxidants may be useful as an adjuvant treatment along with the antimalarial chemotherapeutics to reduce the death rate and enhance the success rate of malaria treatment. CONCLUSION: In this manuscript, an attempt has been made to provide significant insight into the antioxidant activities of herbal extracts against malaria parasites.

An updated patent review on drugs for the treatment of tuberculosis (2018-present).

INTRODUCTION: Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) has been a global challenge as 1.4 million deaths were reported in 2019, which included deaths attributed to HIV-TB co-infection. It is curable by the prescribed Directly Observed Treatment Short (DOTS) course, but the situation becomes critical and alarming due to multi-drug resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. Hence there has been an urgent need to develop novel M.tb chemotherapeutics to overcome this situation. AREAS COVERED: This review provides an overview and update on recent developments on the novel therapeutics for the treatment of TB from the important published and granted patents (2018-present). EXPERT OPINION: The discovery of potent chemotherapeutics with reduced toxicity to combat M.tb particularly MDR and XDR-TB is a major challenge in antitubercular drug development. The missing of any doses during the DOTS treatment and poor immunity particularly in HIV patients has been a major cause for the development of drug resistance. Hence the major focus has to be on novel targets with their inhibitors and novel molecules both of natural and synthetic origins along with repurposed drugs for the complete eradication of tuberculosis.