Novel insights on oral squamous cell carcinoma management using long non-coding RNAs.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent forms of head and neck squamous cell carcinomas (HNSCC) with a poor overall survival rate (about 50%), particularly in cases of metastasis. RNA-based cancer biomarkers are a relatively advanced concept, and non-coding RNAs currently have shown promising roles in the detection and treatment of various malignancies. This review underlines the function of long non-coding RNAs (lncRNAs) in the OSCC and its subsequent clinical implications. LncRNAs, a class of non-coding RNAs, are larger than 200 nucleotides and resemble mRNA in numerous ways. However, unlike mRNA, lncRNA regulates multiple druggable and non-druggable signaling molecules through simultaneous interaction with DNA, RNA, proteins, or microRNAs depending on concentration and localization in cells. Upregulation of oncogenic lncRNAs and down-regulation of tumor suppressor lncRNAs are evident in OSCC tissues and body fluids such as blood and saliva indicating their potential as valuable biomarkers. Targeted inhibition of candidate oncogenic lncRNAs or over-expression of tumor suppressor lncRNAs showed potential therapeutic roles in in-vivo animal models. The types of lncRNAs that are expressed differentially in OSCC tissue and bodily fluids have been systematically documented with specificity and sensitivity. This review thoroughly discusses the biological functions of such lncRNAs in OSCC cell survival, proliferation, invasion, migration, metastasis, angiogenesis, metabolism, epigenetic modification, tumor immune microenvironment, and drug resistance. Subsequently, we addressed the diagnostic and therapeutic importance of lncRNAs in OSCC pre-clinical and clinical systems, providing details on ongoing research and outlining potential future directions for advancements in this field. In essence, this review could be a valuable resource by offering comprehensive and current insights into lncRNAs in OSCC for researchers in fundamental and clinical domains.

miRVim: Three-dimensional miRNA Structure Database.

INTRODUCTION: MicroRNAs (miRNAs), a distinct category of non-coding RNAs, exert multifaceted regulatory functions in a variety of organisms, including humans, animals, and plants. The inventory of identified miRNAs stands at approximately 60,000 among all species, and 1,926 in Homo sapiens manifest miRNA expression. METHOD: Their theranostic role has been explored by researchers over the last few decades, positioning them as prominent therapeutic targets as our understanding of RNA targeting advances. However, the limited availability of experimentally determined miRNA structures has constrained drug discovery efforts relying on virtual screening or computational methods, including machine learning and artificial intelligence. RESULTS: To address this lacuna, miRVim has been developed, providing a repository of human miRNA structures derived from both two-dimensional (MXFold2, CentroidFold, and RNAFold) and three-dimensional (RNAComposer and 3dRNA) structure prediction algorithms, in addition to experimentally available structures from the RCSB PDB repository. miRVim contains 13,971 predicted secondary structures and 17,045 predicted three-dimensional structures, filling the gap of unavailability of miRNA structure data bank. This database aims to facilitate computational data analysis for drug discovery, opening new avenues for advancing technologies, such as machine learning-based predictions in the field of RNA biology. CONCLUSION: The publicly accessible structures provided by miRVim, available at https://mirna.in/miRVim, offer a valuable resource for the research community, advancing the field of miRNA-related computational analysis and drug discovery.

Cefiderocol susceptibility endows hope in treating carbapenem-resistant Pseudomonas aeruginosa: insights from in vitro and in silico evidence.

'High-risk' hypermutable clones of Pseudomonas aeruginosa disseminating extensive drug-resistance (XDR) have raised global health concerns with escalating mortality rates in immunocompromised patients. Mutations in conventional drug-targets under antibiotic stress necessitate structural understanding to formulate sustainable therapeutics. In the present study, the major ß-lactam antibiotic target, penicillin-binding protein-3 (PBP3) with mutations F533L and T91A, were identified in carbapenemase-positive P. aeruginosa isolates (n = 6) using whole genome sequencing. Antibiotic susceptibility tests showed susceptibility to cefiderocol (MIC ≤ 4 µg ml-1) despite pan-ß-lactam resistance in the isolates. Both the mutations reduced local intra-chain interactions in PBP3 that marginally increased the local flexibility (∼1%) in the structures to affect antibiotic-interactions. Molecular dynamics simulations confirmed the overall stability of the PBP3 mutants through root-mean square deviations, radius of gyration, solvent-accessibility and density curves, which favored their selection. Docking studies unveiled that the mutations in PBP3 elicited unfavorable stereochemical clashes with the conventional antibiotics thereby increasing their inhibition constants (IC) up to ∼50 fold. It was deciphered that cefiderocol retained its susceptibility despite mutations in PBP3, due to its higher average binding affinity (ΔG: -8.2 ± 0.4 kcal mol-1) towards multiple PBP-targets and lower average binding affinity (ΔG: -6.7 ± 0.7 kcal mol-1) to ß-lactamases than the other ß-lactam antibiotics. The molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area calculations further indicated energetically favorable binding for cefiderocol with PBP3 proteins. The study gave structural insight into emerging non-polar amino acid substitutions in PBP3 causing XDR and recommends prioritizing available antibiotics based on multi-target affinities to overcome challenges imposed by target-protein mutations.

Designing multi-epitope vaccine against human cytomegalovirus integrating pan-genome and reverse vaccinology pipelines.

Human cytomegalovirus (HCMV) is accountable for high morbidity in neonates and immunosuppressed individuals. Due to the high genetic variability of HCMV, current prophylactic measures are insufficient. In this study, we employed a pan-genome and reverse vaccinology approach to screen the target for efficient vaccine candidates. Four proteins, envelope glycoprotein M, UL41A, US23, and US28, were shortlisted based on cellular localization, high solubility, antigenicity, and immunogenicity. A total of 29 B-cell and 44 T-cell highly immunogenic and antigenic epitopes with high global population coverage were finalized using immunoinformatics tools and algorithms. Further, the epitopes that were overlapping among the finalized B-cell and T-cell epitopes were linked with suitable linkers to form various combinations of multi-epitopic vaccine constructs. Among 16 vaccine constructs, Vc12 was selected based on physicochemical and structural properties. The docking and molecular simulations of VC12 were performed, which showed its high binding affinity (-23.35 kcal/mol) towards TLR4 due to intermolecular hydrogen bonds, salt bridges, and hydrophobic interactions, and there were only minimal fluctuations. Furthermore, Vc12 eliciting a good response was checked for its expression in Escherichia coli through in silico cloning and codon optimization, suggesting it to be a potent vaccine candidate.

Integrating pan-genome and reverse vaccinology to design multi-epitope vaccine against Herpes simplex virus type-1.

Herpes simplex virus type-1 (HSV-1), the etiological agent of sporadic encephalitis and recurring oral (sometimes genital) infections in humans, affects millions each year. The evolving viral genome reduces susceptibility to existing antivirals and, thus, necessitates new therapeutic strategies. Immunoinformatics strategies have shown promise in designing novel vaccine candidates in the absence of a clinically licensed vaccine to prevent HSV-1. However, to encourage clinical translation, the HSV-1 pan-genome was integrated with the reverse-vaccinology pipeline for rigorous screening of universal vaccine candidates. Viral targets were screened from 104 available complete genomes. Among 364 proteins, envelope glycoprotein D being an outer membrane protein with a high antigenicity score (> 0.4) and solubility (> 0.6) was selected for epitope screening. A total of 17 T-cell and 4 B-cell epitopes with highly antigenic, immunogenic, non-toxic properties and high global population coverage were identified. Furthermore, 8 vaccine constructs were designed using different combinations of epitopes and suitable linkers. VC-8 was identified as the most potential vaccine candidate regarding chemical and structural stability. Molecular docking revealed high interactive affinity (low binding energy: - 56.25 kcal/mol) of VC-8 with the target elicited by firm intermolecular H-bonds, salt-bridges, and hydrophobic interactions, which was validated with simulations. Compatibility of the vaccine candidate to be expressed in pET-29(a) + plasmid was established by in silico cloning studies. Immune simulations confirmed the potential of VC-8 to trigger robust B-cell, T-cell, cytokine, and antibody-mediated responses, thereby suggesting a promising candidate for the future of HSV-1 prevention. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-04022-6.

Whole genome analysis reveals unique traits of SARS-CoV-2 in pediatric patients.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to challenge the global healthcare with emerging variants and higher infectivity as well as morbidities. This study investigated potential age-related variations through genomic characterization of the virus under common clinical settings. A cohort comprising 71 SARS-CoV-2 strains from both infected infants and accompanying adults, diagnosed via RT-PCR at a tertiary pediatric hospital and research center, underwent Illumina paired-end sequencing. The subsequent analysis involved standard genomic screening, phylogeny construction, and mutational analyses. The analyzed SARSCoV- 2 strains were compared with globally circulating variants. The overall distribution revealed 67.61 % Delta, 25.7 % Omicron, and 1 % either Kappa or Alpha variants. In 2021, Delta predominated at âˆ¼ 94 %, with Alpha/Kappa accounting for around 5 %. However, in 2022, over 94 % of the samples were Omicron variants, signifying a substantial shift from Delta dominance. Delta variants constituted 69.5 % of infections in adults and 78.5 % in infants, while Omicron variants were responsible for 31 % of cases in infants and 18 % in adults. The Spike region harbored the majority of mutations, with T19R being the most prevalent mutation in the Delta lineage. Notably, the frequencies of this mutation varied between infants and adults. In Omicron samples, G142D emerged as the most prevalent mutation. Our dataset predominantly featured clade 21A and lineage B.1.617.2. This study underscores the differential clinical presentations and genomic characteristics of SARS-CoV-2 in pediatric patients and accompanying adults. Understanding the dynamic evolution of the SARS- CoV-2 in both pediatric and adults can help in strengthening prophylactic measures.

Changing Landscape of Antimicrobial Resistance in Neonatal Sepsis: An in silico Analyses of Multidrug Resistance in Klebsiella pneumoniae.

BACKGROUND: Neonatal sepsis poses a critical healthcare concern, as multidrug-resistant Klebsiella pneumoniae ( K. pneumoniae ) infections are on the rise. Understanding the antimicrobial susceptibility patterns and underlying resistance mechanism is crucial for effective treatment. OBJECTIVES: This study aimed to comprehensively investigate the antimicrobial susceptibility patterns of K. pneumoniae strains responsible for neonatal sepsis using in silico tools. We sought to identify trends and explore reasons for varying resistance levels, particularly for ß-lactams and fluoroquinolone. METHODS: K. pneumoniae isolated from neonates at Kanchi Kamakoti CHILDS Trust Hospital (2017-2020) were analyzed for antimicrobial resistance. Elevated resistance to ß-lactam and fluoroquinolone antibiotics was further investigated through molecular docking and interaction analysis. ß-lactam affinity with penicillin-binding proteins and ß-lactamases was examined. Mutations in ParC and GyrA responsible for quinolone resistance were introduced to investigate ciprofloxacin interactions. RESULTS: Of 111 K. pneumoniae blood sepsis isolates in neonates, high resistance was detected to ß-lactams such as cefixime (85.91%, n = 71), ceftriaxone (84.9%, n = 106), cefotaxime (84.9%, n = 82) and fluoroquinolone (ciprofloxacin- 79.44%, n = 107). Molecular docking revealed low ß-lactam binding toward penicillin-binding proteins and higher affinities for ß-lactamases, attributing to the reduced ß-lactam efficiency. Additionally, ciprofloxacin showed decreased affinity toward mutant ParC and GyrA in comparison to their corresponding wild-type proteins. CONCLUSION: Our study elucidates altered resistance profiles in neonatal sepsis caused by K. pneumoniae , highlighting mechanisms of ß-lactam and fluoroquinolone resistance. It underscores the urgent need for the development of sustainable therapeutic alternatives to address the rising antimicrobial resistance in neonatal sepsis.

Coinfections in human papillomavirus associated cancers and prophylactic recommendations.

The Human Papillomavirus (HPV) infection is responsible for more than 80% of reported cervical cancer and other virus-associated tumours. Although this global threat can be controlled using effective vaccination strategies, a growing perturbation of HPV infection is an emerging coinfection likely to increase the severity of the infection in humans. Moreover, these coinfections prolong the HPV infections, thereby risking the chances for oncogenic progression. The present review consolidated the clinically significant microbial coinfections/co-presence associated with HPV and their underlying molecular mechanisms. We discussed the gaps and concerns associated with demography, present vaccination strategies, and other prophylactic limitations. We concluded our review by highlighting the potential clinical as well as emerging computational intervention measures to kerb down HPV-associated severities.

Impact of PmrB mutations on clinical Klebsiella pneumoniae with variable colistin-susceptibilities: Structural insights and potent therapeutic solutions.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections continue to impose high morbidity threats to hospitalized patients worldwide, limiting therapeutic options to last-resort antibiotics like colistin. However, the dynamic genomic landscape of colistin-resistant K. pneumoniae (COLR-Kp) invoked ardent exploration of underlying molecular signatures for therapeutic propositions/designs. We unveiled the structural impact of the widespread and emerging PmrB mutations involved in colistin resistance (COLR) in K. pneumoniae. In the present study, clinical isolates of K. pneumoniae expressed variable susceptibilities to colistin (>0.5 µg/mL for resistant and ≤0.25 µg/mL for susceptible) despite mutations such as T157P, G207D and T246A. The protein sequences extracted from in-house sequenced genomes were used to model mutant PmrB proteins and analyze the underlying structural alterations. The mutations were contrasted based on molecular dynamics simulation trajectories, free-energy landscapes and structural flexibility profiles. The altered backbone flexibilities can be an essential factor for mutant selection by COLR K. pneumoniae and can provide clues to deal with emerging mutants. Furthermore, PmrB having high druggability confidence (>0.99), was explored as a potential target for 1396 virtually screened FDA-approved drug candidates. Among the top-10 compounds (scores >70), amphotericin B was found to be potential candidate with high affinity (Binding energy <-8 kcal/mol) and stable interactions (RMSF <0.7 Å) against PmrB druggable pockets, despite the mutations, which encourages future adjunct therapeutic research against COLR-Kp.

Structure Elucidation and Interaction Dynamics of MefA-MsrD Efflux Proteins in Streptococcus pneumoniae: Impact on Macrolide Susceptibility.

Macrolides are empirically used to treat bacterial community-acquired pneumonia (CAP). Streptococcus pneumoniae, being the major pathogen responsible for bacterial CAP with high mortality rates, express MefA-MsrD efflux pumps to hinder macrolide susceptibility. Despite its importance, the structural features of the efflux-protein complex and its impact on macrolide susceptibility have not yet been elucidated explicitly. Therefore, in the present study, combining homology, threading, and dynamics approaches, MefA and MsrD proteins in pathogenic S. pneumoniae were modeled. Both membrane (lipid-bilayer) and cytoplasmic (aqueous) environments were considered to simulate the MefA and MsrD proteins in their ideal cellular conditions followed by dynamics analyses. The simulated MefA structure represented a typical major facilitator superfamily protein structure with 13 transmembrane helices. MefA-MsrD interaction via clustering-based docking revealed low-energy conformers with stable intermolecular interactions. The higher clinical MIC value of azithromycin over erythromycin was reflected upon erythromycin eliciting stronger interactions (dissociation constant or ki = ∼52 µM) with the cytoplasmic ATP-binding MsrD than azithromycin (ki = ∼112 µM). The strong (binding energy = -132.1 ± 9.5 kcal/mol) and highly stable (root-mean-square fluctuation < 1.0 Å) physical association between MefA with MsrD was validated and was found to be unaffected by the antibiotic binding. Higher propensity of the macrolides to interact with MsrD than MefA established the importance of the former in macrolide susceptibility. Ours is probably the first report on the structural arrangements in the MefA-MsrD efflux complex and the macrolide susceptibility in S. pneumoniae. This study provides a novel lead for experimental explorations and efflux-pump inhibitor designs.

Non-Coding RNAs in Oral Cancer: Emerging Roles and Clinical Applications.

Oral cancer (OC) is among the most prevalent cancers in the world. Certain geographical areas are disproportionately affected by OC cases due to the regional differences in dietary habits, tobacco and alcohol consumption. However, conventional therapeutic methods do not yield satisfying treatment outcomes. Thus, there is an urgent need to understand the disease process and to develop diagnostic and therapeutic strategies for OC. In this review, we discuss the role of various types of ncRNAs in OC, and their promising clinical implications as prognostic or diagnostic markers and therapeutic targets. MicroRNA (miRNA), long ncRNA (lncRNA), circular RNA (circRNA), PIWI-interacting RNA (piRNA), and small nucleolar RNA (snoRNA) are the major ncRNA types whose involvement in OC are emerging. Dysregulated expression of ncRNAs, particularly miRNAs, lncRNAs, and circRNAs, are linked with the initiation, progression, as well as therapy resistance of OC via modulation in a series of cellular pathways through epigenetic, transcriptional, post-transcriptional, and translational modifications. Differential expressions of miRNAs and lncRNAs in blood, saliva or extracellular vesicles have indicated potential diagnostic and prognostic importance. In this review, we have summarized all the promising aspects of ncRNAs in the management of OC.

Revisiting the Role of CD63 as Pro-Tumorigenic or Anti-Tumorigenic Tetraspanin in Cancers and its Theragnostic Implications.

Cluster of differentiation antigen 63 (CD63) belongs to a superfamily of proteins, usually defined as tetraspanins which are known to transverse the bilayer membranes four times. The expression of CD63 has been shown to get altered in several cancers, where it has been demonstrated to act as both a tumor promoter and tumor suppressor. The present review describes the mechanism of how CD63 promotes tumor formation in certain cancer types while inhibiting in some other specific cancers. Glycosylation, a post-translational process plays a significant role in regulating the expression and function of these membrane proteins. Being a crucial exosomal flag protein, CD63 has been found to get involved in endosomal cargo sorting as well as the production of extracellular vesicles. Increased expression of exosomal CD63 derived from advanced tumors has demonstrated its role in promoting metastasis. CD63 also regulates the characteristic and function of stem cells on which they get expressed. This particular tetraspanin has been discovered to participate in gene fusion to perform distinctive roles in certain specific cancer types like breast cancer and pigmented epithelioid melanocytoma. Furthermore, this review mentions twelve different microRNAs obtained from miRDB that might target CD63. A few theragnostic uses of this membrane protein are also discussed. Thereby, the review indicates that further studies on CD63 might prove it to be an effective therapeutic target in different cancers in the coming future.

Impact of the COVID-19 pandemic on routine vaccine landscape: A global perspective.

The coronavirus disease (COVID-19) threat is subsiding through extensive vaccination worldwide. However, the pandemic imposed major disruptions in global immunization programs and has aggravated the risks of vaccine-preventable disease (VPD) outbreaks. Particularly, lower-middle-income regions with minimal vaccine coverage and circulating vaccine-derived viral strains, such as polio, suffered additional burden of accumulated zero-dose children, further making them vulnerable to VPDs. However, there is no compilation of routine immunization disruptions and recovery prospects. There is a noticeable change in the routine vaccination coverage across different phases of the pandemic in six distinct global regions. We have summarized the impact of COVID-19 on routine global vaccination programs and also identified the prospects of routine immunization to combat COVID-like outbreaks.

Design, Synthesis, and Biological Evaluation of Novel Quercetin Derivatives as PPAR-γ Partial Agonists by Modulating Epithelial-Mesenchymal Transition in Lung Cancer Metastasis.

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR-γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR-γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR-γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2-furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR-γ partial activation. QDs-treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI-H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E-box binding homeobox 1) and concomitant upregulation of epithelial marker (E-cadherin).

Partial Activation of PPAR-γ by Synthesized Quercetin Derivatives Modulates TGF-ß1-Induced EMT in Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) has a very low survival rate due to poor response to chemotherapy and late detection. Epithelial to mesenchymal transition (EMT) is regarded as a major contributor to drive metastasis during NSCLC progression. Towards this, transforming growth factor-beta 1 (TGF-ß1) is the key driver that endows cancer cells with increased aggressiveness. Recently, this group synthesized a series of Schiff base quercetin derivatives (QDs) and ascertained their effectiveness on EMT markers of A549 cell line. This study evidenced that the EMT process is counteracted via the partial activation of a nuclear hormone receptor, Peroxisome proliferator-activated receptor (PPAR)-γ through QDs. Here, that work is extended to investigate the interplay between PPAR-γ partial activation and TGF-ß1-induced EMT in human lung cancer A549 cells. The results reveal that TGF-ß1 plays a critical role in suppressing PPAR-γ, which is markedly reversed and increased by partial agonists: QUE2FH and QUESH at both protein and transcriptional levels. The partial agonists not only stimulate PPAR-γ in a balanced manner but also prevent the loss of E-cadherin and acquisition of TGF-ß1-induced mesenchymal markers (Snail, Slug, Vimentin, and Zeb-1). Subsequently, the effects are accompanied by attenuation of TGF-ß1-induced migratory ability of A549 cells.

Bioactive phytocompounds against specific target proteins of Borrelia recurrentis responsible for louse-borne relapsing fever: Genomics and structural bioinformatics evidence.

Louse-borne relapsing fever (LBRF) with high untreated mortality caused by spirochete Borrelia recurrentis is predominantly endemic to Sub-Saharan Africa and has re-emerged in parts of Eastern Europe, Asia and Latin America due to population migrations. Despite subtractive evolution of lice-borne pathogenic Borrelia spp. from tick-borne species, there has been no comprehensive report on conservation of protein targets across tick and lice-borne pathogenic Borrelia nor exploration of phytocompounds that are toxic to tick against lice. From the 19 available whole genomes including B. recurrentis, B. burgdorferi, B. hermsii, B. parkeri and B. miyamotoi, conservation of seven drug targets (>80% domain identity) viz. 30 S ribosomal subunit proteins (RSP) S3, S7, S8, S14, S19, penicillin-binding protein-2 and 50 S RSP L16 were deciphered through multiple sequence alignments. Twelve phytocompounds (hydroxy-tyrosol, baicalein, cis-2-decanoic acid, morin, oenin, rosemarinic acid, kaempferol, piceatannol, rottlerin, luteolin, fisetin and monolaurin) previously explored against Lyme disease spirochete B. burgdorferi when targeted against LBRF-causing B. recurrentis protein targets revealed high multi-target affinity (2%-20% higher than conventional antibiotics) through molecular docking. However, based on high binding affinity against all target proteins, stable coarse-grained dynamics (fluctuations <1 Å) and safe pharmacological profile, luteolin was prioritized. The study encourages experimental evaluation of the potent phytocompounds and similar protocols for investigating other emerging vector-borne diseases.

Genomics and structural insight into the masking of gentamicin-resistance in clinical Burkholderia pseudomallei strain VB29710 from India.

The present study reported a rare gentamicin-susceptible ß-lactamase (PenA, OXA-57) expressing clinical Burkholderia pseudomallei isolate VB29710 from India. Whole-genome sequencing and structural analyses revealed the insertion of R962 and L963 into AmrB, the transmembrane-protein of the AmrAB-OprA efflux-pump that affected aminoglycoside-efflux through local alterations in backbone conformation.

Exploring binding mode assessment of novel kaempferol, resveratrol, and quercetin derivatives with PPAR-α as potent drug candidates against cancer.

Peroxisome proliferator-activated receptors (PPAR)-α, a ligand-activated transcription factor stands out to be a valuable protein target against cancer. Given that ligand binding is the crucial process for the activation of PPAR-α, fibrate class of synthetic compounds serves as potent agonist for the receptor. However, their serious side effects limit the long-term application in cancer. This emphasizes the dire need to identify new candidates that would exert desired activation by abrogating the adverse effects caused by synthetic agonists. Natural dietary products serve as an important source of drug discovery. Hence, the present study encompasses the investigation of the role of natural plant phenolic compounds: kaempferol, resveratrol, and quercetin and their 8708 derivatives by the means of computational pipeline comprising molecular docking and molecular dynamic (MD) simulation techniques. Docking calculations shortlisted potential candidates, namely 6-cinnamylchrysin (6-CC), resveratrol potassium-4-sulfate (RPS) and 6-[2-(3,4-Dihydroxyphenyl)-5-hydroxy-4-oxochromen-7-yl]oxyhexyl nitrate (DHOON), and derivatives of kaempferol, resveratrol, and quercetin, respectively. 6-CC, RPS, and DHOON manifested better affinities of - 32.83 kcal/mol (Ala333, Lys358, His440), - 27.22 kcal/mol (Tyr314, Met355), and - 30.18 kcal/mol (Ser280, Tyr314, Ala333), respectively, and were found to act as good stimulants for PPAR-α. Among these three compounds, 6-CC caused relatively least deviations and fluctuations analyzed through MD simulation which judiciously held responsible to attain most favorable interaction with PPAR-α. Followed by the binding free energy (ΔG) calculations using MM-GBSA confirmed the key role of 6-CC toward PPAR-α. The compound 6-CC also achieved high drug-likeness and pharmacokinetic properties. Thus, these findings stipulate new drug leads for PPAR-α receptor which abets a way to develop new anti-cancer drugs.

Synergistic combination of ritonavir and cisplatin as an efficacious therapy in human cervical cancer cells: a computational drug discovery and in vitro insight.

HIV-protease inhibitor Ritonavir (RTV) is a clinical-stage drug. We exhibit here the synergistic effect of RTV coupled with cisplatin as potential combination therapy for treatment of cervical cancer. Knowledge about the interaction of RTV with the high-expression signatures in cancer is limited. Therefore, we utilized computational techniques to understand and assess the drug-binding affinity and drug-target interaction of RTV with these altered protein signatures. Computational studies revealed the potential interaction ability of RTV along with few other HIV protease inhibitors against these altered cancer targets. All targets exhibited good affinity towards RTV and the highest affinity was exhibited by CYP450 3A4, PDGFR and ALK. RTV established stable interaction with PDGFR and molecular dynamics simulation confirms their frequent interaction for 300 ns. Control docking of PDGFR with standard PDGFR inhibitor exhibited lower binding affinity when compared with RTV-PDGFR complex. In search of drugs as a part of combination therapy to reduce side effects of Cisplatin, this paper further evaluated the effect of combination of RTV and Cisplatin in cervical cancer cells. We propose several combination models that combines anti-viral drug RTV and standard chemotherapeutic agent, Cisplatin to be synergistic with CI value ranging from of 0.01 to 1.14. These observations suggest that anti-viral compound (RTV) could act synergistically with Cisplatin for cervical cancer therapy. However, further studies are warranted to investigate the combinatorial mode of action of RTV and Cisplatin on different molecular pathways to have a translational outcome in cervical cancer.Communicated by Ramaswamy H. Sarma.