A Gut-Wrenching Feeling: Overcoming Cognitive Biases in an Atypical Presentation of Chronic Mesenteric Ischemia.

Chronic mesenteric ischemia is a rare but serious condition that can present with a variety of symptoms, including abdominal pain, diarrhea, and weight loss. Our case report presents a 63-year-old male with a past medical history of generalized anxiety disorder, Barrett's esophagus, hypertension, hyperlipidemia, chronic obstructive pulmonary disease (COPD) with active smoking who initially presented with severe diffuse abdominal pain, nausea, vomiting, and chronic diarrhea resulting in malnutrition and 40-pound weight loss over a six-month span. The patient underwent extensive diagnostic evaluation and was diagnosed with Yersinia gastroenteritis via gastroenteritis panel (GI Panel), explaining all of the patient's symptoms. The patient underwent treatment for said gastroenteritis but did not experience remission of symptoms, leading to further diagnostic evaluations; a definitive diagnosis was not found, yet the patient's symptoms persisted. The patient then underwent extensive serologic and endoscopic evaluation, after extensive imaging and diagnostic work-up, the patient was finally diagnosed with chronic mesenteric ischemia (CMI) of the superior mesenteric artery (SMA) with severe celiac and inferior mesenteric artery (IMA) stenosis. The patient initially underwent stenting (7 mm by 26 mm Balloon Mounted LifestreamTM Covered Stent; Becton Dickson (BD); Franklin Lakes, NJ, USA), which provided temporary relief to his symptoms, however, the relief did not last long. Upon reimaging, the patient was found to have stenosis of the stent, leading to the eventual placement of a bare-metal stent (ExpressTM LD 7 x 27 mm balloon mounted bare-metal stent; Boston Scientific; Boston, MA, USA) across the celiac artery as well as the placement of an IMA stent (InnovaTM Self-expanding 5 x 20 mm bare-metal stent; Boston Scientific). This eventually resulted in the resolution of the patient's symptoms, eventual weight gain, and improvement in quality of life.

Synchronous Liver Abscess With Cholecystitis: A Rare Case of Initial Presentation of Gallbladder Cancer Posing a Diagnosis Challenge.

Gallbladder carcinoma (GBC) is the most common of all biliary tract cancers. GBC is a multifactorial disease. Gallbladder dysplasia from any gallbladder inflammatory condition is one of the main risk factors for GBC. The late diagnosis of GBC is a major problem in its treatment. It is treated by radical resection and the prognosis is improved by adjuvant chemoradiation. We present a rare case of gall bladder cancer presenting as hepatic abscesses with severe sepsis. An 83-year-old male presented with progressive symptoms of shakiness, general weakness, vomiting, and profuse diarrhea. Lab work revealed deranged liver enzymes. Computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) abdomen revealed intrahepatic abscesses contiguous with the gallbladder lumen through a gallbladder wall defect and cholecystitis of unknown chronicity. Subsequently, he underwent central hepatectomy and the pathology report of the sample as well as endoscopic retrograde cholangiopancreatography (ERCP) brushings revealed gallbladder adenocarcinoma. The case was complicated by biloma, acute renal failure, and the development of malignant ascites, and the patient died almost four months after the diagnosis of gallbladder cancer.

Antiandrogen enzalutamide induced genetic, cellular, and hepatic damages: amelioration by triterpene Lupeol.

Androgen deprivation therapy is commonly used for the treatment of prostate cancer. Enzalutamide is a next-generation androgen receptor inhibitor, initially approved to treat castration-resistance prostate cancer. Lupeol, a triterpene present in various fruits, vegetables, has anti-oxidant and anti-proliferative activity. The present study aimed to evaluate the Enzalutamide-induced toxicity and its possible amelioration by Lupeol. We performed multiple in vitro and in vivo experiments to conclude our hypothesis. The results revealed that both Enzalutamide and Lupeol interact with DNA through electrostatic interactions. Enzalutamide (5-20 µM) caused cytotoxicity in both normal (PNT2) and cancer cells (LNCaP and 22Rv1). However, Lupeol (10-50 µM) specifically killed the cancer cells while sparing normal cells. The study further revealed that Lupeol could attenuate Enzalutamide-induced cytotoxicity and genotoxicity (chromosomal aberrations and micronucleus formation) to normal cells and potentially induce cytotoxicity to transformed cells. We further observed that Lupeol (40 mg/kg) mediated attenuation of the Enzalutamide (10 mg/kg) induced oxidative and DNA damages. Our study also revealed that Lupeol reverses the Enzalutamide-induced hepatic and renal damages. In conclusion, our study indicates that Lupeol can be used as an adjuvant for reducing the toxic effects and enhancing the effectiveness of Enzalutamide.

Thrombotic Thrombocytopenic Purpura and Metastatic Malignancy-Like Presentation Secondary to Hypervirulent Strain of Klebsiella pneumoniae: A Case Series.

Thrombotic thrombocytopenic purpura (TTP) is a rare and potentially fatal disease. The majority of cases are caused by a significant enzyme deficiency in the blood called the von Willebrand factor (VWF) cleaving protease (also called ADAMTS13). TTP is classified as a hematologic emergency because of the high mortality rate. The diagnosis is difficult due to the extensive overlap in the clinical manifestations of TTP and other illnesses. Klebsiella pneumoniae infection can in very rare instances present with TTP and/or a metastatic-like presentation where the patient might have prostate, liver, brain, and lung abscesses mimicking late-stage solid organ malignancy. In this paper, we report a case of TTP secondary to Klebsiella pneumoniae infection in a 38-year-old male patient, who presented with fever, cough, and shortness of breath for five days. On examination, he was vitally unstable, confused, and not oriented, with a Glasgow Coma Scale (GCS) of 9/15. Complete blood count (CBC) showed a high white blood cell (WBC) count, very low platelet count, increased reticulocyte count, and significant elevation of schistocytes on peripheral blood film. Sputum and blood cultures were positive for Klebsiella pneumoniae. Computerized tomography (CT) scan chest showed bilateral lung parenchymal nodules. An abdominal ultrasound (US) scan detected a right hepatic lobe lesion that was both cystic and solid. The patient was initially started on meropenem, vancomycin, and levofloxacin due to shock presentation which was de-escalated to ceftriaxone later. The patient had five therapeutic plasma exchange sessions and was started on methylprednisolone for three days. The patient's situation gradually improved, and he was discharged later on. The second case is a 63-year-old-male patient who presented with fever, dry cough, night sweats, and dysuria for seven days. He was vitally stable, conscious, alert, and oriented. His hemoglobin was 9.6 g/dl. He was scheduled for an urgent colonoscopy to rule out colon cancer along with computed tomography (CT) scan of the chest, abdomen, and pelvis. The CT scan showed complex cystic lesions involving the right hepatic lobe, lungs, adrenal glands, and prostate. The clinical picture was suggestive of hyper-mucoid Klebsiella pneumoniae infection showering to the liver, adrenal glands, and prostate. A drained prostate collection and urine cultures confirmed the diagnosis. The patient was managed with surgical drainage of the collection in addition to ceftriaxone and metronidazole. The patient was discharged in good health on ciprofloxacin with follow-up as an outpatient.

A Rare Case of Pseudomembrane-Associated Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic, life-long inflammatory bowel disease that normally presents with bloody diarrhea, fever, abdominal pain, and leukocytosis. Diagnosis is usually based on clinical presentation, endoscopy with biopsy, and exclusion of alternative diagnoses. In very rare cases, pseudomembranes may be found on colonoscopy in patients with an early UC flare. Historically, the objective finding of pseudomembranes has been exclusively used to diagnose a Clostridioides difficile infection (CDI); however, diagnostic testing must be correctly utilized to confirm whether a CDI is truly the cause of the presence of pseudomembranes, and not an alternative etiology, such as UC. In this case, we discuss a 43-year-old female who presented to the hospital with worsening chronic bloody diarrhea after being seen in the outpatient clinic for a questionable CDI. She underwent endoscopic evaluation revealing pseudomembranous colitis; however, C. difficile testing showed one positive gastrointestinal (GI) pathogen panel and multiple negative antigens and toxin enzyme immunoassays (EIA). With a clinical suspicion of early UC, the patient was treated with mesalamine enemas and improved clinically before discharge. Several months later, she underwent endoscopic evaluation with biopsy, which showed findings consistent with a diagnosis of UC.

DAVS-NET: Dense Aggregation Vessel Segmentation Network for retinal vasculature detection in fundus images.

In this era, deep learning-based medical image analysis has become a reliable source in assisting medical practitioners for various retinal disease diagnosis like hypertension, diabetic retinopathy (DR), arteriosclerosis glaucoma, and macular edema etc. Among these retinal diseases, DR can lead to vision detachment in diabetic patients which cause swelling of these retinal blood vessels or even can create new vessels. This creation or the new vessels and swelling can be analyzed as biomarker for screening and analysis of DR. Deep learning-based semantic segmentation of these vessels can be an effective tool to detect changes in retinal vasculature for diagnostic purposes. This segmentation task becomes challenging because of the low-quality retinal images with different image acquisition conditions, and intensity variations. Existing retinal blood vessels segmentation methods require a large number of trainable parameters for training of their networks. This paper introduces a novel Dense Aggregation Vessel Segmentation Network (DAVS-Net), which can achieve high segmentation performance with only a few trainable parameters. For faster convergence, this network uses an encoder-decoder framework in which edge information is transferred from the first layers of the encoder to the last layer of the decoder. Performance of the proposed network is evaluated on publicly available retinal blood vessels datasets of DRIVE, CHASE_DB1, and STARE. Proposed method achieved state-of-the-art segmentation accuracy using a few number of trainable parameters.

Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells.

We explored whether the anti-prostate cancer (PC) activity of the androgen receptor-axis-targeted agents (ARATs) abiraterone and enzalutamide is enhanced by metformin. Using complementary biological and molecular approaches, we determined the associated underlying mechanisms in pre-clinical androgen-sensitive PC models. ARATs increased androgren receptors (ARs) in LNCaP and AR/ARv7 (AR variant) in VCaP cells, inhibited cell proliferation in both, and induced poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and death in VCaP but not LNCaP cells. Metformin decreased AR and ARv7 expression and induced cleaved PARP-1-associated death in both cell lines. Metformin with abiraterone or enzalutamide decreased AR and ARv7 expression showed greater inhibition of cell proliferation and greater induction of cell death than single agent treatments. Combination treatments led to increased cleaved PARP-1 and enhanced PARP-1 activity manifested by increases in poly(ADP-ribose) (PAR) and nuclear accumulation of apoptosis inducing factor (AIF). Enhanced annexin V staining occurred in LNCaP cells only with metformin/ARAT combinations, but no caspase 3 recruitment occurred in either cell line. Finally, metformin and metformin/ARAT combinations increased lysosomal permeability resulting in cathepsin G-mediated PARP-1 cleavage and cell death. In conclusion, metformin enhances the efficacy of abiraterone and enzalutamide via two PARP-1-dependent, caspase 3-independent pathways, providing a rationale to evaluate these combinations in castration-sensitive PC.

Extracellular Volume in Primary Mitral Regurgitation.

OBJECTIVES: This study used cardiovascular magnetic resonance (CMR) to evaluate whether elevated extracellular volume (ECV) was associated with mitral valve prolapse (MVP) or if elevated ECV was a consequence of remodeling independent of primary mitral regurgitation (MR) etiology. BACKGROUND: Replacement fibrosis in primary MR is more prevalent in MVP; however, data on ECV as a surrogate for diffuse interstitial fibrosis in primary MR are limited. METHODS: Patients with chronic primary MR underwent comprehensive CMR phenotyping and were stratified into an MVP cohort (>2 mm leaflet displacement on a 3-chamber cine CMR) and a non-MVP cohort. Factors associated with ECV and replacement fibrosis were assessed. The association of ECV and symptoms related to MR and clinical events (mitral surgery and cardiovascular death) was ascertained. RESULTS: A total of 424 patients with primary MR (229 with MVP and 195 non-MVP) were enrolled. Replacement fibrosis was more prevalent in the MVP cohort (34.1% vs. 6.7%; p < 0.001), with bi-leaflet MVP having the strongest association with replacement fibrosis (odds ratio: 10.5; p < 0.001). ECV increased with MR severity in a similar fashion for both MVP and non-MVP cohorts and was associated with MR severity but not MVP on multivariable analysis. Elevated ECV was independently associated with symptoms related to MR and clinical events. CONCLUSIONS: Although replacement fibrosis was more prevalent in MVP, diffuse interstitial fibrosis as inferred by ECV was associated with MR severity, regardless of primary MR etiology. ECV was independently associated with symptoms related to MR and clinical events. (DeBakey Cardiovascular Magnetic Resonance Study [DEBAKEY-CMR]; NCT04281823).

Guidelines and Recommendations for Tonometry Use during the COVID-19 Era.

The novel coronavirus disease COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a substantial change in eye care and clinical practice. There has been conflicting information and weak evidence on the virus's transmission through tears. Yet, virus detection on cornea and conjunctiva surface as a gateway for infection is not well-studied. Moreover, there have been no reported cases of SARS-CoV-2 transmission through tonometry to date. Thus, this uncertainty has urged this review on evidence-based guidelines and recommendations on tonometer use in the COVID-19 era. The aim of this article is to provide ophthalmologists with recommendations for tonometry practice based on current evidence and best practice guidelines.

Natural History of Functional Tricuspid Regurgitation Quantified by Cardiovascular Magnetic Resonance.

BACKGROUND: Quantitation of tricuspid regurgitant (TR) severity can be challenging with conventional echocardiographic imaging and may be better evaluated using cardiovascular magnetic resonance (CMR). OBJECTIVES: In patients with functional TR, this study sought to examine the relationship between TR volume (TRVol) and TR fraction (TRF) with all-cause mortality. METHODS: We examined 547 patients with functional TR using CMR to quantify TRVol and TRF. The primary outcome was all-cause mortality. Thresholds for mild, moderate, and severe TR were derived based on natural history outcome data. RESULTS: During a median follow-up of 2.6 years (interquartile range: 1.7 to 3.3 years), there were 93 deaths, with an estimated 5-year survival of 79% (95% confidence interval [CI]: 73% to 83%). After adjustment of clinical and imaging variables, including RV function, both TRF (adjusted hazard ratio [AHR] per 10% increment: 1.26; 95% CI: 1.10 to 1.45; p = 0.001) and TRVol (AHR per 10-ml increment: 1.15; 95% CI: 1.04 to 1.26; p = 0.004) were associated with mortality. Patients in the highest-risk strata of TRVol ≥45 ml or TRF ≥50% had the worst prognosis (AHR: 2.26; 95% CI: 1.36 to 3.76; p = 0.002 for TRVol and AHR: 2.60; 95% CI: 1.45 to 4.66; p = 0.001 for TRF). CONCLUSIONS: This is the first study to use CMR to assess independent prognostic implications of functional TR. Both TRF and TRVol were associated with increased mortality after adjustment for clinical and imaging covariates, including right ventricular ejection fraction. A TRVol of ≥45 ml or TRF of ≥50% identified patients in the highest-risk strata for mortality. These CMR thresholds should be used for patient selection in future trials to determine if tricuspid valve intervention improves outcomes in this high-risk group.

Nanomedicines in Diagnosis and Treatment of Cancer: An Update.

Nanomedicine has revolutionized the field of cancer detection and treatment by enabling the delivery of imaging agents and therapeutics into cancer cells. Cancer diagnostic and therapeutic agents can be either encapsulated or conjugated to nanosystems and accessed to the tumor environment through the passive targeting approach (EPR effect) of the designed nanomedicine. It may also actively target the tumor exploiting conjugation of targeting moiety (like antibody, peptides, vitamins, and hormones) to the surface of the nanoparticulate system. Different diagnostic agents (like contrast agents, radionuclide probes and fluorescent dyes) are conjugated with the multifunctional nanoparticulate system to achieve simultaneous cancer detection along with targeted therapy. Nowadays targeted drug delivery, as well as the early cancer diagnosis is a key research area where nanomedicine is playing a crucial role. This review encompasses the significant recent advancements in drug delivery as well as molecular imaging and diagnosis of cancer exploiting polymer-based, lipid-based and inorganic nanoparticulate systems.

Apigenin, A Plant Flavone Playing Noble Roles in Cancer Prevention Via Modulation of Key Cell Signaling Networks.

BACKGROUND: Cancer is a global health problem and the continuous rise in incidence and mortality due to cancer carries a real economic burden to all countries. Accumulation of genetic mutation, exposure of environmental carcinogens and food habits due to change in lifestyles are the key reasons for cancer. Targeting cancer cells, we need a multitargeting molecule with low/no toxicity. OBJECTIVE: To review the current update of the research status of chemopreventive/therapeutic molecule, Apigenin. METHODS: Compare the results of the published articles and granted patents on this compound. We also discuss the pros and cons of the present research and future direction. RESULTS: Cancer cells have characteristic alterations and dysregulation of various cell signaling pathways that control cell homeostasis, proliferation, motility, and survival in normal cells. Natural flavonoids are the compounds well known for their anti-inflammatory, anti-oxidant, and anti-cancerous properties. Apigenin, along with several other physiological effects, has a very low intrinsic toxicity and striking effects on the proliferation of cancer cells. Interestingly, this multitargeting molecule is getting wide acceptance among researchers. It is evident from the recent patents filed in this compound. At present, three patents have been granted only on the anticancer properties of apigenin. CONCLUSION: This mini-review will explain the present research status of apigenin and will further shine some light on how apigenin performs its anti-cancerous actions by interfering with the key cellsignaling pathways.

PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges.

Triple-negative breast cancer (TNBC) is a highly malignant subtype of breast cancer associated with poor prognosis. Although conventional chemotherapy regimens have shown some effectiveness in early TNBC cases, the outcome in advanced stages is poor. The PI3K/AKT/mTOR pathway is one of the important and active pathways involved in chemoresistance and survival of TNBC. This pathway is speculated to play an important part in malignant transformation and has been considered as a potential molecular target for the design of therapeutic agents to treat TNBC. This review discusses the potentials and drug discovery perspectives of PI3K/AKT/mTOR as a therapeutic target for effective management of TNBC with anticipated challenges.

Ethical and religious dilemmas of modern reproductive choices and the Islamic perspective.

Advances in the field of Assisted Reproductive Technologies (ART) are constantly evolving, starting from Artificial Insemination (AI) and in-vitro fertilization (IVF), to the current state of the art technologies that enable embryo biopsy for Pre-implantation Genetic Testing (PGT). The future includes gene mapping and DNA replacement technologies with the potential for the so-called "designer babies." In other words, shortly, a modern couple may be in a position to decide how to procreate and with whom; which pregnancy to keep and which one to terminate depending on their prior knowledge about the pregnancy and the available choices. This article addresses the moral, ethical, legal and religious dilemmas as a result of these technological advances in the field of ART and how these new challenges are addressed theologically in the Islamic world where the state law is strongly influenced by religion. This article sets out to discuss relevant issues and dilemmas but does not seek to prioritize or promote any opinion or view over any other religion/sect, ethical or legal opinion or view.

Plasmid DNA vaccine coding eight repeats of gonadotrophin-releasing hormone induced atrophy of prostate in male mice.

BACKGROUND: Prostate hyperplasia and neoplasia are major illness of men and elderly dogs. Treatment of prostate cancer requires androgen deprivation surgery or therapy to prevent metastases and alleviate pain. Recently, six DNA vaccines have entered clinical trials against prostate cancer in humans with limited success. There is a need for new therapies that delay the establishment of malignancy and prolong survival. MATERIALS AND METHODS: A plasmid DNA vaccine coding for eight gonadotrophin-releasing hormone (GnRH-I) interspersed in eight T-helper epitopes was used. Sexually mature male mice were immunized with the vaccine in hemagglutinating virus of Japanese envelope vector and boosted in nonionized surfactant vesicles in study weeks 0, 3, 6, 9, and 12. Plasma anti-GnRH-I antibody response, serum testosterone concentration, and effect on prostate were evaluated. RESULTS: Results of an indirect enzyme linked immunosorbent assay (ELISA) showed anti-GnRH-I antibody response (OD value) detected in the study week 3 (0.613 ± 0.179) with a highest response in the week 12 (1.205 ± 0.219). Serum testosterone concentration (ng/ml) in vaccinated mice was significantly reduced (P > 0.000, 0.761 ± 0.531) in the study week 24 in contrast to control serum (7.583 ± 1.251). Group average gross combined weight of prostate and seminal vesicles of vaccinated mice was significantly (P < 0.000) reduced in the study week 24 (319.75 ± 89.19 mg) in contrast to control weight (563.25 ± 108.60 mg). Sections of prostate stained with Goldner's trichrome showed profuse pink color secretion in control tubules, which however was absent in the vaccinated prostate. The lining epithelium of the vaccinated prostate was atrophied and did not enfold in its lumen. CONCLUSIONS: Immunization strategy designed with the plasmid DNA vaccine in hemagglutinating virus of Japanese envelope and nonionized surfactant vesicles can be the genetic immunization platform. This vaccine bears potentials in terms of reducing serum testosterone concentration and induction of atrophy of prostate. Targeted ablation of native GnRH-I by genetic immunization could offer leverage to vaccinologists, seeking therapeutic target to control and prevent malignancy of prostate.

Rationalising drug delivery using nanoparticles: a combined simulation and immunology study of GnRH adsorbed to silica nanoparticles.

Silica nanoparticles (SiNPs) have been shown to have significant potential for drug delivery and as adjuvants for vaccines. We have simulated the adsorption of GnRH-I (gonadotrophin releasing hormone I) and a cysteine-tagged modification (cys-GnRH-I) to model silica surfaces, as well as its conjugation to the widely-used carrier protein bovine serum albumin (BSA). Our subsequent immunological studies revealed no significant antibody production was caused by the peptide-SiNP systems, indicating that the treatment was not effective. However, the testosterone response with the native peptide-SiNPs indicated a drug effect not found with cys-GnRH-I-SiNPs; this behaviour is explained by the specific orientation of the peptides at the silica surface found in the simulations. With the BSA systems, we found significant testosterone reduction, particularly for the BSA-native conjugates, and an antibody response that was notably higher with the SiNPs acting as an adjuvant; this behaviour again correlates well with the epitope presentation predicted by the simulations. The range of immunological and hormone response can therefore be interpreted and understood by the simulation results and the presentation of the peptides to solution, paving the way for the future rational design of drug delivery and vaccine systems guided by biomolecular simulation.

Detection of clostridium difficile antigen and toxin in stool specimens: Comparison of the C. difficile quik chek complete enzyme immunoassay and GeneXpert C. difficile polymerase chain reaction assay.

BACKGROUND/AIMS: Accurate and rapid laboratory diagnosis of Clostridium difficile infections (CDI) remains a significant challenge. A two-step algorithm for detection of toxigenic C. difficile in stool based on initial screening for glutamate dehydrogenase assay followed by confirmation by toxin A+B detection using an enzyme immunoassay (EIA) or molecular assay has been proposed. We aimed to evaluate the C. difficile Quik Chek Complete® (QCC-EIA) versus the GeneXpert® C. difficile polymerase chain reaction (PCR) assay in this two-step algorithm. MATERIALS AND METHODS: Two hundred and ten liquid stool samples obtained between June 2014 and June 2015 from patients suspected of CDI were tested by the QCC-EIA and GeneXpert PCR assay. The GeneXpert assay was used as the reference standard to calculate the QCC-EIA sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Of the 210 stool samples tested, 43 (20.5%) were positive by QCC-EIA, while 31 (14.8%) were positive by GeneXpert assay. The sensitivity and specificity of the QCC-EIA were found to be 100 and 93%, respectively; the PPV and NPV were 72 and 100%, respectively. The binary toxin was detected in 12 (38.7%) and tcdC gene deletion in 3 (9.6%). CONCLUSIONS: The low specificity of QCC-EIA makes it less reliable as a confirmatory test for CDI diagnosis. This test may be used as a screening test in a two-step algorithm when combined with a molecular assay or another confirmatory test.

Inhibition of DNA Topoisomerase Type IIα (TOP2A) by Mitoxantrone and Its Halogenated Derivatives: A Combined Density Functional and Molecular Docking Study.

In this study, mitoxantrone and its halogenated derivatives have been designed by density functional theory (DFT) to explore their structural and thermodynamical properties. The performance of these drugs was also evaluated to inhibit DNA topoisomerase type IIα (TOP2A) by molecular docking calculation. Noncovalent interactions play significant role in improving the performance of halogenated drugs. The combined quantum and molecular mechanics calculations revealed that CF3 containing drug shows better preference in inhibiting the TOP2A compared to other modified drugs.

Non-covalent interactions involving halogenated derivatives of capecitabine and thymidylate synthase: a computational approach.

Capecitabine, a fluoropyrimidine prodrug, has been a frequently chosen ligand for the last one and half decades to inhibit thymidylate synthase (TYMS) for treatment of colorectal cancer. TYMS is a key enzyme for de novo synthesis of deoxythymidine monophosphate and subsequent synthesis of DNA. Recent years have also seen the trait of modifying ligands using halogens and trifluoromethyl (-CF3) group to ensure enhanced drug performance. In this study, in silico modification of capecitabine with Cl, Br, I atoms and -CF3 group has been performed. Density functional theory has been employed to optimize the drug molecules and elucidate their thermodynamic and electrical properties such as Gibbs free energy, enthalpy, electronic energy, dipole moment and frontier orbital features (HOMO-LUMO gap, hardness and softness). Flexible and rigid molecular docking have been implemented between drugs and the receptor TYMS. Both inter- and intra-molecular non-covalent interactions involving the amino acid residues of TYMS and the drug molecules are explored in details. The drugs were superimposed on the resolved crystal structure (at 1.9 Å) of ZD1694/dUMP/TYMS system to shed light on similarity of the binding of capecitabine, and its modifiers, to that of ZD1694. Together, these results may provide more insights prior to synthesizing halogen-directed derivatives of capecitabine for anticancer treatment.