Evaluation of Pharmacy Intern Interventions on Antimicrobial Use in University-Affiliated Hospitals: A Retrospective Analysis.

Background: Appropriate use of antimicrobials is essential to enhance therapeutic safety and efficacy. Clinical pharmacists play a crucial role in optimizing antimicrobial use; however, the contribution of pharmacy interns in antimicrobial use has not been studied. The objective of this study was to ascertain the quantity and nature of interventions related to antimicrobials documented by pharmacy interns, along with the rates at which physicians accepted these interventions. Methods: From August 2017 to March 2022, this study retrospectively evaluated antimicrobial-related interventions recorded by pharmacy interns during their rotations at King Khalid University. The categories of interventions included medication selection, addition of antimicrobials, dose or frequency adjustments, medication discontinuation, de-escalation, therapeutic drug monitoring, and others. Statistical analysis was conducted to identify patterns and correlations. Results: This study evaluated 1295 antimicrobial-related interventions, with high physician acceptance rates of 91.6% and 4.0% accepted with modifications. The most frequent interventions were dose/frequency adjustments (36.3%) and medication discontinuation (23%). Vancomycin, colistin, and meropenem were the most frequently intervened antimicrobials. Documented clinical outcomes included enhancing treatment efficacy (37.3%), reducing treatment toxicity (26.81%), and avoiding unnecessary antimicrobial exposure (21.8%). Significant correlations were observed between hospital units and intervention types, indicating unit-specific intervention patterns. Conclusions: Theses findings highlight the vital role of pharmacy interns in optimizing antimicrobial therapy. Future research should focus on evaluating the long-term clinical and economic benefits of their involvement.

Factors associated with applicant performance on the Saudi Pharmacist Licensure Examination (SPLE).

Background: Limited data are available on factors that are associated with passing rates for the Saudi Pharmacist Licensure Examination (SPLE). The aim of this study is to investigate student characteristics and academic performance characteristics that may predict their success on SPLE. Methods: This was a single-institution retrospective cohort study, which included pharmacy graduates from 2019 to 2021. Demographic, academic, and SPLE data were collected for each graduate. Binary logistic regression was used to explore the association between potential predictors and first-time SPLE pass status. A stepwise regression was then performed to develop multiple logistic models. Results: A total of 494 graduates were included in the study. Females, PharmD graduates, and on-time graduation had higher odds of passing SPLE (P = 0.0065, P = 0.0003, and P < 0.0001, respectively). For each 0.5 increase in GPA, the odds of passing SPLE increase by 3.5 times (OR 3.53; 95 % CI, 2.83-4.42; P < 0.0001). Of the tests taken prior to university admission, the overall high school score, general aptitude test (GAT) score, and qualifying score were significantly associated with higher SPLE first-time pass rates. When multiple logistic regression analysis was performed, GPA and GAT scores were the only significant predictors for higher SPLE first-time pass rates (P < 0.0001 and P = 0.0002, respectively). Conclusion: The current research has shown that there is an association between higher SPLE first-time pass rates and several factors, most importantly the GPA and GAT score. Further research is needed, as it has the potential to inform the decision when reviewing pharmacy admission criteria.

Choline chloride/urea as a green and efficient deep eutectic solvent in three-component and four-component synthesis of novel pyrazole and pyrano[2,3-c] pyrazole derivatives with antibacterial and antifungal activity.

In this study, choline chloride/urea was used as a green deep eutectic solvent in the three-component reaction of hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrazole derivatives, and in the four-component reaction of methyl/ethyl acetoacetate, hydrazine/phenylhydrazine, malononitrile, and aromatic aldehydes for synthesizing pyrano[2,3-c]pyrazole derivatives. Elemental analysis, 1H, and 13C NMR spectroscopy were used to confirm the structure of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives. The antimicrobial effects of the synthesized pyrazole and pyrano[2,3-c] pyrazole derivatives were investigated. In antimicrobial tests, instructions from clinical and laboratory standards institutes were used. Antimicrobial study was done on pathogenic gram-positive and gram-negative species, and specialized aquatic strains and fungal species. Using choline chloride/urea, novel pyrazole derivatives and pyrano[2,3-c]pyrazole derivatives were synthesized, and other derivatives were synthesized with higher efficiency in less time than some previously reported methods. MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) obtained for derivatives were higher than some antibiotic drugs. Synthesis and reports of new derivatives of pyrazole and pyrano[2,3-c]pyrazole, and investigation and reports of their antimicrobial properties on gram-positive, gram-negative, and specialized aquatic and fungal species are among the novel and important findings of this study.

Co-Delivery of Naringin and Ciprofloxacin by Oleic Acid Lipid Core Encapsulated in Carboxymethyl Chitosan/Alginate Nanoparticle Composite for Enhanced Antimicrobial Activity.

A novel combination of antibiotic, ciprofloxacin (CIP) with herbal counterpart naringin (NAR) was encapsulated by an oleic acid lipid core and carboxymethyl chitosan (CM-CS)/Alginate (AG) nanoparticle composite (CIP + NAR-CM-CS/AG-NPs) for improved antimicrobial efficacy of antibiotic. Herein, this study explored the design and preparation of a composite system that enables to deliver both CIP and NAR from the oleic acid lipid core of CM-CS/AG nanoparticles using a nonsolvent ionic gelation technique. The nanoparticles (NPs) were fabricated with improved long-acting antimicrobial activity against E. coli and S. aureus. The optimized composition was investigated for physicochemical properties particle size, particle distribution, and ζ-potential. A diverse array of analytical tools was employed to characterize the optimized formulation including DSC, XRD, Malvern Zetasizer for particle size, ζ-potential, TEM, and SEM. Further, the preparation was investigated for % drug release, flux determination, antioxidant, and antimicrobial activity. The formulation stability was tested for 90 days and also evaluated formulation stability in fetal bovine serum to inspect the modification in physicochemical characteristics. NPs size was determined at 85 nm, PDI, and ζ-potential was recorded at 0.318, and 0.7 ± 0.4 mV. The % CIP and NAR entrapment efficiency and % loading were incurred as 91 ± 1.9, and 89.5 ± 1.2; 11.5 ± 0.6, and 10.8 ± 0.5%, respectively. The drug release erupted in the beginning phase followed by sustained and prolonged release for 48 h. The analytical experiments by DSC ensured the noninteracting and safe use of excipients in combination. X-ray studies demonstrated the amorphous state of the drug in the formulation. The insignificant alteration of formulation characteristics in FBS suggested stable and robust preparation. Storage stability of the developed formulation ensured consistent and uniform stability for three months. The DPPH assays demonstrated that NAR had good antioxidant capacity and supported improving antimicrobial activity of CIP. The hemolytic test suggested the developed formulation was compatible and caused insignificant RBC destruction. The in-house built formulation CIP + NAR-CM-CS/AG-NPs significantly improved the antimicrobial activity compared to CIP alone, offering a novel choice in antimicrobial application.

Bedaquiline-Loaded Solid Lipid Nanoparticles Drug Delivery in the Management of Non-Small-Cell Lung Cancer (NSCLC).

Non-small-cell lung cancer (NSCLC) mortality and new case rates are both on the rise. Most patients have fewer treatment options accessible due to side effects from drugs and the emergence of drug resistance. Bedaquiline (BQ), a drug licensed by the FDA to treat tuberculosis (TB), has demonstrated highly effective anti-cancer properties in the past. However, it is difficult to transport the biological barriers because of their limited solubility in water. Our study developed a UPLC method whose calibration curves showed linearity in the range of 5 ng/mL to 500 ng/mL. The UPLC method was developed with a retention time of 1.42 and high accuracy and precision. Its LOQ and LOD were observed to be 10 ng/mL and 5 ng/mL, respectively, whereas in the formulation, capmul MCM C10, Poloxamer 188, and PL90G were selected as solid lipids, surfactants, and co-surfactants, respectively, in the development of SLN. To combat NSCLC, we developed solid lipid nanoparticles (SLNs) loaded with BQ, whereas BQ suspension is prepared by the trituration method using acacia powder, hydroxypropyl methylcellulose, polyvinyl acrylic acid, and BQ. The developed and optimized BQ-SLN3 has a particle size of 144 nm and a zeta potential of (-) 16.3 mV. whereas BQ-loaded SLN3 has observed entrapment efficiency (EE) and loading capacity (LC) of 92.05% and 13.33%, respectively. Further, BQ-loaded suspension revealed a particle size of 1180 nm, a PDI of 0.25, and a zeta potential of -0.0668. whereas the EE and LC of BQ-loaded suspension were revealed to be 88.89% and 11.43%, respectively. The BQ-SLN3 exhibited insignificant variation in particle size, homogeneous dispersion, zeta potential, EE, and LC and remained stable over 90 days of storage at 25 °C/60% RH, whereas at 40 °C/75% RH, BQ-SLN3 observed significant variation in the above-mentioned parameters and remained unstable over 90 days of storage. Meanwhile, the BQ suspension at both 25 °C (60% RH) and 40 °C (75% RH) was found to be stable up to 90 days. The optimized BQ-SLN3 and BQ-suspension were in vitro gastrointestinally stable at pH 1.2 and 6.8, respectively. The in vitro drug release of BQ-SLN3 showed 98.19% up to 12 h at pH 7.2 whereas BQ suspensions observed only 40% drug release up to 4 h at pH 7.2 and maximum drug release of >99% within 4 h at pH 4.0. The mathematical modeling of BQ-SLN3 followed first-order release kinetics followed by a non-Fickian diffusion mechanism. After 24 to 72 h, the IC50 value of BQ-SLN3 was 3.46-fold lower than that of the BQ suspension, whereas the blank SLN observed cell viability of 98.01% and an IC50 of 120 g/mL at the end of 72 h. The bioavailability and higher biodistribution of BQ-SLN3 in the lung tumor were also shown to be greater than those of the BQ suspension. The effects of BQ-SLN3 on antioxidant enzymes, including MDA, SOD, CAT, GSH, and GR, in the treated group were significantly improved and reached the level nearest to that of the control group of rats over the cancer group of rats and the BQ suspension-treated group of rats. Moreover, the pharmacodynamic activity resulted in greater tumor volume and tumor weight reduction by BQ-SLN3 over the BQ suspension-treated group. As far as we are aware, this is the first research to look at the potential of SLN as a repurposed oral drug delivery, and the results suggest that BQ-loaded SLN3 is a better approach for NSCLC due to its better action potential.

Emergence of Nano-Based Formulations for Effective Delivery of Flavonoids against Topical Infectious Disorders.

Flavonoids are hydroxylated phenolic substances in vegetables, fruits, flowers, seeds, wine, tea, nuts, propolis, and honey. They belong to a versatile category of natural polyphenolic compounds. Their biological function depends on various factors such as their chemical structure, degree of hydroxylation, degree of polymerization conjugation, and substitutions. Flavonoids have gained considerable attention among researchers, as they show a wide range of pharmacological activities, including coronary heart disease prevention, antioxidative, hepatoprotective, anti-inflammatory, free-radical scavenging, anticancer, and anti-atherosclerotic activities. Plants synthesize flavonoid compounds in response to pathogen attacks, and these compounds exhibit potent antimicrobial (antibacterial, antifungal, and antiviral) activity against a wide range of pathogenic microorganisms. However, certain antibacterial flavonoids have the ability to selectively target the cell wall of bacteria and inhibit virulence factors, including biofilm formation. Moreover, some flavonoids are known to reverse antibiotic resistance and enhance the efficacy of existing antibiotic drugs. However, due to their poor solubility in water, flavonoids have limited oral bioavailability. They are quickly metabolized in the gastrointestinal region, which limits their ability to prevent and treat various disorders. The integration of flavonoids into nanomedicine constitutes a viable strategy for achieving efficient cutaneous delivery owing to their favorable encapsulation capacity and diminished toxicity. The utilization of nanoparticles or nanoformulations facilitates drug delivery by targeting the drug to the specific site of action and exhibits excellent physicochemical stability.

Pharmacological and Clinical Efficacy of Picrorhiza kurroa and Its Secondary Metabolites: A Comprehensive Review.

Traditional remedies for the treatment of various ailments are gaining popularity. Traditionally, one of the most valuable therapeutic herbs has been Picrorhiza kurroa Royle ex Benth. Traditional and folk uses of P. kurroa include chronic constipation, skin-related problems, burning sensation, chronic reoccurring fever, jaundice, heart problems, breathing, digestion, allergy, tuberculosis, blood-related problems, prediabetes and obesity, laxative, cholagogue, and liver stimulatory. Phytoconstituents such as glycosides, alkaloids, cucurbitacins, iridoids, phenolics, and terpenes in P. kurroa have shown promising pharmacological potential. In order to uncover novel compounds that may cure chronic illnesses, such as cardiovascular, diabetes, cancer, respiratory, and hepatoprotective diseases, the screening of P. kurroa is essential. This study comprehensively evaluated the ethnopharmacological efficacy, phytochemistry, pharmacological activity, dose, and toxicity of P. kurroa. This review provides comprehensive insights into this traditional medication for future research and therapeutic application. The purpose of this review article was to determine the pharmacological effects of P. kurroa on a variety of disorders. P. kurroa may be a natural alternative to the standard treatment for eradicating newly evolving diseases. This study is intended as a resource for future fundamental and clinical investigations.

Comparison of Saudi Pharmacist Licensure Examination (SPLE) Pass Rates by Institution and Applicant Characteristics.

In 2019, the Saudi Pharmacist Licensure Examination (SPLE) was first administered to all pharmacy graduates and served as one of the prerequisites for obtaining a pharmacist license. The objective of this study was to evaluate whether institution and applicant characteristics are associated with first-time SPLE success. Passing status for 2284 SPLE first-time applicants was obtained from online public data for the years 2019 and 2020. The data included applicant sex, institution type (public vs. private), and college establishment year (2006 or earlier vs. after 2006). Overall, the SPLE first-time pass rate in 2020 was significantly higher than in 2019 (98.0 vs. 95.9%; p = 0.0062). Applicants from pharmacy colleges established in or before 2006 had a higher SPLE first-time pass rate, compared to those from pharmacy colleges established after 2006 (98.2 vs. 95.2%; p < 0.0001). The pass rate for male applicants was lower compared to female applicants (95.8 vs. 97.5%; p = 0.0221). The results of logistic regression showed that exam year (2020 vs. 2019), applicant sex (female vs. male), and pharmacy college establishment year (≤2006 vs. >2006) were statistically significant predictors. Further studies are needed in the upcoming years when more cumulative data are available.

Identification of PARP12 Inhibitors By Virtual Screening and Molecular Dynamics Simulations.

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12.

In Vitro Evaluation of Antioxidant, Anticancer, and Anti-Inflammatory Activities of Ethanolic Leaf Extract of Adenium obesum.

Adenium obesum commonly known as "desert rose" belongs to the family Apopcynaceae and has previously been reported for its anti-influenza, antimicrobial, and cytotoxic efficacies and well-known for their ethno-medicinal applications. In the present study, ethanolic extracts of A. obesum (AOE) were analyzed by gas chromatography-mass spectrometry (GC-MS) to identify the important phytochemical compounds. The GC-MS analysis of AOE detected the presence of 26 phytochemical compounds. This plant is traditionally used for the treatment of various diseases. In this report, the antioxidant, anti-inflammatory, and anticancer activities of ethanolic leaf extract from A. obesum (AOE) were studied. The antioxidant potential of ethanolic extract of AOE was examined by different antioxidant assays, such as antioxidant capacity by the DPPH, ABTS, superoxide, hydroxyl radical scavenging, and lipid peroxidation inhibition assays. The antioxidant activities of various reaction mixtures of AOE were compared with a reference or standard antioxidant (ascorbic acid). In addition, we also evaluated the anticancer activity of AOE, and it was observed that AOE was found to be cytotoxic against A549 lung cancer cells. It was found that AOE inhibited the viability of A549 lung cancer cells by inducing nuclear condensation and fragmentation. Furthermore, ethanolic AOE demonstrated the anti-inflammatory potential of AOE in murine alveolar macrophages (J774A.1) as an in vitro model system. AOE showed its potential in reducing the levels of inflammatory mediators including the proinflammatory cytokines and TNF-α. The results obtained in the present investigation established the antioxidant, anticancer, and anti-inflammatory potency of AOE, which may account for subsequent studies in the formulation of herbal-based medicine.

Antiproliferative and apoptotic potential of Glycyrrhizin against HPV16+ Caski cervical cancer cells: A plausible association with downreguation of HPV E6 and E7 oncogenes and Notch signaling pathway.

Cervical cancer (CCa) is the second most frequent carcinoma in females and human papilloma virus (HPV) oncoproteins are regarded as one of the critical etiological agent. Despite recent advances in screening and management of CCa, still it remains the deadliest carcinoma as advanced and metastatic stages are mostly incurable. This urges for the development of newer therapeutic interventions. The current was aimed to investigate the antiproliferative and apoptotic potential of glycyrrhizin (Gly) against HPV16+ CaSki CCa cells. Our findings substantiated that Gly exerted antiproliferative effects on the CaSki cells by obstructing their proliferation rate. Gly substantially enhanced apoptosis in Caski cells in a dose-dependent manner via augmenting the generation of ROS, DNA fragmentation and disruption of the mitochondrial membrane potential. Gly mediated apoptosis in CaSki cells was found to be due to activation of caspase-8 and capsase-9 along with the modulation of pro-and anti-apoptotic gene expression. Moreover, Gly halts the progression of CaSki cells at G0/G1 phase which was found to be due to reduced expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) along with the enhanced expression of CDK inhibitor p21Cip1. Further, Gly downregulates the expression of HPV oncoproteins (E6 & E7) along with the inhibition of Notch signaling pathway. Taken together, Gly represents as a potential therapeutic modality for CCa which could rapidly be translated for clinical studies.

Investigation of Antidepressant Properties of Yohimbine by Employing Structure-Based Computational Assessments.

The use of pharmaceuticals to treat Major Depressive Disorder (MDD) has several drawbacks, including severe side effects. Natural compounds with great efficacy and few side effects are in high demand due to the global rise in MDD and ineffective treatment. Yohimbine, a natural compound, has been used to treat various ailments, including neurological conditions, since ancient times. Serotonergic neurotransmission plays a crucial role in the pathogenesis of depression; thus, serotonergic receptor agonist/antagonistic drugs are promising anti-depressants. Yohimbine was investigated in this study to determine its antidepressant activity using molecular docking and pharmacokinetic analyses. Additionally, the in silico mutational study was carried out to understand the increase in therapeutic efficiency using site-directed mutagenesis. Conformational changes and fluctuations occurring during wild type and mutant serotonergic receptor, 5-hydroxytryptamine receptors 1A (5HT1A) and yohimbine were assessed by molecular dynamics MD simulation studies. Yohimbine was found to satisfy all the parameters for drug-likeness and pharmacokinetics analysis. It was found to possess a good dock score and hydrogen-bond interactions with wild type 5HT1A structure. Our findings elaborate the substantial efficacy of yohimbine against MDD; however, further bench work studies may be carried out to prove the same.

Swertia chirayita suppresses the growth of non-small cell lung cancer A549 cells and concomitantly induces apoptosis via downregulation of JAK1/STAT3 pathway.

Lung carcinoma is the leading cause of cancer-related mortalities worldwide, and present therapeutical interventions are not successful enough to treat this disease in many cases. Recent years have witnessed a surge in exploring natural compounds for their antiproliferative efficacy to expedite the characterization of novel anticancer chemotherapeutics. Swertia chirayita is a valued medicinal herb and possess intrinsic pharmaceutical potential. However, elucidation of its anticancer effects at molecular levels remains unclear and needs to be investigated. We assessed the anticancer and apoptotic efficacy of S. chirayita ethanolic extract (Sw-EtOH) on non-small cell lung cancer (NSCLC) A549 cells during this exploratory study. The results elucidated that S. chirayita extract induced toxic effects within lung cancer cells by ~1 fold during cytotoxicity and LDH release assay at a 400 µg/ml concentration. Sw-EtOH extract elevates the level of ROS, resulting in the disruption of Δψm and release of cytosolic cytochrome c by 3.15 fold. Activation of caspases-3, -8 & -9 also escalated by ~1 fold, which further catalyze the augmentation of PARP cleavage (~3 folds), resulting in a four-fold increase in Sw-EtOH induced apoptosis. The gene expression analysis further demonstrated that Sw-EtOH extracts inhibited JAK1/STAT3 signaling pathway by down-regulating the levels of JAK1 and STAT3 to nearly half a fold. Treatment of Sw-EtOH modulates the expression level of various STAT3 associated proteins, including Bcl-XL, Bcl-2, Mcl-1, Bax, p53, Fas, Fas-L, cyclinD1, c-myc, IL-6, p21 and p27 in NSCLC cells. Thus, our study provided a strong impetus that Sw-EtOH holds the translational potential of being further evaluated as efficient cancer therapeutics and a preventive agent for the management of NSCLC.

Computational Screening of Natural Compounds for Identification of Potential Anti-Cancer Agents Targeting MCM7 Protein.

Minichromosome maintenance complex component 7 (MCM7) is involved in replicative licensing and the synthesis of DNA, and its overexpression is a fascinating biomarker for various cancer types. There is currently no effective agent that can prevent the development of cancer caused by the MCM7 protein. However, on the molecular level, inhibiting MCM7 lowers cancer-related cellular growth. With this purpose, this study screened 452 biogenic compounds extracted from the UEFS Natural Products dataset against MCM protein by using the in silico art of technique. The hit compounds UEFS99, UEFS137, and UEFS428 showed good binding with the MCM7 protein with binding energy values of -9.95, -8.92, and -8.71 kcal/mol, which was comparatively higher than that of the control compound ciprofloxacin (-6.50). The hit (UEFS99) with the minimum binding energy was picked for molecular dynamics (MD) simulation investigation, and it demonstrated stability at 30 ns. Computational prediction of physicochemical property evaluation revealed that these hits are non-toxic and have good drug-likeness features. It is suggested that hit compounds UEFS99, UEFS137, and UEFS428 pave the way for further bench work validation in novel inhibitor development against MCM7 to fight the cancers.

Work readiness scale for pharmacy interns and graduates: A cross-sectional study.

INTRODUCTION: As the number of unemployment among pharmacy graduates increases, the Saudi Ministry of Labor implemented extra measures to facilitate their training and hiring by the private sectors. Nevertheless, there is a paucity of data regarding pharmacy graduates' work readiness (WR). Hence, we aim to assess their WR and identify predicting factors associated with WR among pharmacy graduates' in Saudi Arabia. METHODS: A 46-item self-reported pre-validated anonymous work readiness scale (WRS) survey with a 5-point Likert scale was administered to pharmacy senior students and graduates using Qualtrics XM® survey tool over the month of May 2020. The main outcome was to assess WRS for pharmacy interns and graduates and identify factors associated with work readiness. RESULTS: A total of 617 participants have participated in this survey, out of which 46.5% were freshly graduated pharmacists and 19.6% were pharmacy interns. Most participants (82.3%) were PharmD candidates or graduates. Around two-third of participants (63%) have successfully completed all survey items. The maximum points scored was 223 out of 230, and the median overall score was found to be 175. There was no significant association with gender, age, or type of university regarding overall scores. However, a statistically significant odds ratio was observed with PharmD program type and previous pharmaceutical marketing training (OR = 1.778, 95% CI = 1.143-2.765: OR = 0.618, 95% CI = 0.432-0.884, respectively). CONCLUSION: The overall median score shows a good work readiness level among pharmacy students/graduates in Saudi Arabia; however, PharmD program graduates exposed to advance pharmacy training, including the pharmaceutical marketing experience, have higher work readiness odds than Bpharm graduates. Further studies involving other related perspectives, such as stakeholders, employers, and preceptors, would give a clear image of pharmacy graduates' job readiness levels.

Identification of 3-((1-(Benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrazine-2-carboxylic Acid as a Potential Inhibitor of Non-Nucleosidase Reverse Transcriptase Inhibitors through InSilico Ligand- and Structure-Based Approaches.

Non-nucleosidase reverse transcriptase inhibitors (NNRTIs) are highly promising agents for use in highly effective antiretroviral therapy. We implemented a rational approach for the identification of promising NNRTIs based on the validated ligand- and structure-based approaches. In view of our state-of-the-art techniques in drug design and discovery utilizing multiple modeling approaches, we report here, for the first time, quantitative pharmacophore modeling (HypoGen), docking, and in-house database screening approaches in the identification of potential NNRTIs. The validated pharmacophore model with three hydrophobic groups, one aromatic ring group, and a hydrogen-bond acceptor explains the interactions at the active site by the inhibitors. The model was implemented in pharmacophore-based virtual screening (in-house and commercially available databases) and molecular docking for prioritizing the potential compounds as NNRTI. The identified leads are in good corroboration with binding affinities and interactions as compared to standard ligands. The model can be utilized for designing and identifying the potential leads in the area of NNRTIs.

Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach.

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of -7.19, -7.95, and -7.21 kcal/mol for the monomer (K-chain) and -8.05, -9.10, and -7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (-5.83 kcal/mol (monomer) and -5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome.