Sourav Kalra

Pediatric cerebellopontine angle medulloblastomas

Medullobastomas are common tumors in children located usually in cerebellar vermis. In adults also, they present and are likely to be laterally placed. Their incidence in rare sites like cerebellopontine angle is also described. The presentation, neuroradiological appearance, and brief summary of histopathological findings are discussed.

Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors

There are around 20 Cyclin-dependent kinases (CDKs) known till date, and various research groups have reported their role in different types of cancer. The X-ray structures of some CDKs especially CDK2 was exploited in the past few years, and several inhibitors have been found, e.g., flavopiridol, indirubicin, roscovitine, etc., but due to the specificity issues of these inhibitors (binding to all CDKs), these were called as pan inhibitors. The revolutionary outcome of palbociclib in 2015 as CDK4/6 inhibitor added a new charm to the specific inhibitor design for CDKs. Computer-aided drug design (CADD) tools added a benefit to the design and development of new CDK inhibitors by studying the binding pattern of the inhibitors to the ATP binding domain of CDKs. Herein, we have attempted a comparative analysis of structural differences between several CDKs ATP binding sites and their inhibitor specificity by depicting the important ligand-receptor interactions for a particular CDK to be targeted. This perspective provides futuristic implications in the design of inhibitors considering the spatial features and structural insights of the specific CDK.

Toward an Understanding of Structural Insights of Xanthine and Aldehyde Oxidases: An Overview of their Inhibitors and Role in Various Diseases

Almost all drug molecules become the substrates for oxidoreductase enzymes, get metabolized into more hydrophilic products and eliminated from the body. These metabolites sometime may be more potent, active, inactive, or toxic in nature compared to parent molecule. Xanthine oxidoreductase and aldehyde oxidase belong to molybdenum containing family and are well characterized for their structures and functions, in particular to their ability to oxidize/hydroxylate the xenobiotics. Their upregulated clinical levels causing oxidative stress are associated with pathways either directly involved in the progression of diseases, gout, or indirectly with the succession of other diseases such as diabetes, cancer, etc. Herein, we have put forth a comprehensive review on the xanthine and aldehyde oxidases pertaining to their structures, functions, pathophysiological role, and a comparative analysis of structural insights of xanthine and aldehyde oxidases’ binding domains with endogenous ligands or inhibitors. Though both the enzymes are molybdenum containing and are likely to share some common pathways and interact with inhibitors in a similar manner but we have focused on structural prerequisites for inhibitor specificity to both the enzymes keeping in view of the existing X‐ray structures. This review also provides futuristic implications in the design of inhibitors derived from inorganic complexes or small organic molecules considering the spatial features and structural insights of both the enzymes.

Role of Genomic Alterations in HER2 Positive Breast Carcinoma: Focus on Susceptibility and Trastuzumab-therapy

BACKGROUNDnBreast cancer is the most frequently diagnosed life-threatening malignancy among women, across the globe. HER2 positive is a distinct breast cancer subtype, on account of its unique biology and physiological behavior.nnnRESULTSnAmplification of HER2 oncogene/polysomy 17 leads to HER2 overexpression that is a significant causal implication in HER2 positive breast cancer. HER2 gene variants, as well as other genes/gene variants, are involved in its overexpression, disease prognosis and in predicting the susceptibility towards HER2 positive breast cancer. Trastuzumab (Herceptin) is the most commonly used therapy for treating patients with HER2 positive status. Genomic alterations are incriminated in the development of trastuzumab-resistance, which influences the response towards trastuzumab-therapy.nnnCONCLUSIONnIn the current review article, we have summarized the genomic alterations that are responsible for overexpression of HER2 and therefore, increased risk of breast cancer. In addition, the gene variants affecting response towards trastuzumab-therapy have also been discussed.

A review on quinoline derived scaffolds as Anti-HIV Agents

After restricting the proliferation of CD4+T cells, Human Immunodeficiency Virus (HIV), infection persists at a very fast rate causing Acquired Immunodeficiency Syndrome (AIDS). This demands the vigorous need of suitable anti-HIV agents, as existing medicines do not provide a complete cure and exhibit drawbacks like toxicities, drug resistance, side-effects, etc. Even the introduction of Highly Active Antiretroviral Therapy (HAART) failed to combat HIV/AIDS completely. The major breakthrough in anti-HIV discovery was marked with the discovery of raltegravir in 2007, the first integrase (IN) inhibitor. Thereafter, the discovery of elvitegravir, a quinolone derivative emerged as the potent HIV-IN inhibitor. Though many more classes of different drugs that act as anti-HIV have been identified, some of which are under clinical trials, but the recent serious focus is still laid on quinoline and its analogues. In this review, we have covered all the quinoline-based derivatives that inhibit various targets and are potential anti-HIV agents in various phases of the drug discovery.

In silico binding mechanism prediction of benzimidazole based corticotropin releasing factor-1 receptor antagonists by quantitative structure activity relationship, molecular docking and pharmacokinetic parameters calculation

Despite the various research efforts toward the treatment of stress-related disorders, the drug has not yet launched last 20 years. Corticotropin releasing factor-1 receptor antagonists have been point of great interest in stress-related disorders. In the present study, we have selected benzazole scaffold-based compounds as corticotropin releasing factor-1 antagonists and performed 2D and 3D QSAR studies to identify the structural features to elucidating the binding mechanism prediction. The best 2D QSAR model was obtained through multiple linear regression method with r 2 value of .7390, q 2 value of .5136 and pred_r 2 (predicted square correlation coefficient) value of .88. The contribution of 2D descriptor, T_2_C_1 was 60% (negative contribution) and 4pathClusterCount was 40.24% (positive contribution) in enhancing the activity. Also 3D QSAR model was statistically significant with q 2 value of .9419 and q 2_se (standard error of internal validation) value of .19. Statistical parameters results prove the robustness and significance of both models. Further, molecular docking and pharmacokinetic analysis was performed to explore the scope of investigation. Docking results revealed that the all benzazole compounds show hydrogen bonding with residue Asn283 and having same hydrophobic pocket (Phe286, Leu213, Ile290, Leu287, Phe207, Arg165, Leu323, Tyr327, Phe284, and Met206). Compound B14 has higher activity compare to reference molecules. Most of the compounds were found within acceptable range for pharmacokinetic parameters. This work provides the extremely useful leads for structural substituents essential for benzimidazole moiety to exhibit antagonistic activity against corticotropin releasing factor-1 receptors.

Computational investigation of binding mechanism of substituted pyrazinones targeting corticotropin releasing factor-1 receptor deliberated for anti-depressant drug design

Abstract In spite of various research investigations towards anti-depressant drug discovery program, no one drug has not yet launched last 20 years. Corticotropin-releasing factor-1 (CRF-1) is one of the most validated targets for the development of antagonists against depression, anxiety and post-traumatic stress disorders. Various research studies suggest that pyrazinone based CRF-1 receptor antagonists were found to be highly potent and efficacious. In this research investigation, we identified the pharmacophore and binding pattern through 2D and 3D-QSAR and molecular docking respectively. Molecular dynamics studies were also performed to explore the binding pattern recognition. We establish the relationship between activity and pharmacophoric features to design new potent compounds. The best 2D-QSAR model was generated through multiple linear regression method with r2 value of 0.97 and q2 value of 0.89. Also 3D-QSAR model was obtained through k-nearest neighbor molecular field analysis method with q2 value of 0.52 and q2_se value of 0.36. Molecular docking and binding energy were also evaluated to define binding patterns and pharmacophoric groups, including (i) hydrogen bond with residue Asp284, Glu305 and (ii) π–π stacking with residue Trp9. Compound 11i has the highest binding affinity compared to reference compounds, so this compound could be a potent drug for stress related disorders. Most of the compounds, including reference compounds were found within acceptable range of physicochemical parameters. These observations could be provided the leads for the design and optimization of novel CRF-1 receptor antagonists. Communicated by Ramaswamy H. Sarma GRAPHICAL ABSTRACT ABBREVIATIONSCRF corticotropin-releasing factorHPA hypothalamus-pituitary-adrenocortical axiskNN MFA k-nearest neighbor molecular field analysisMD molecular dynamicsMLR multiple linear regressionMM/GBSA molecular mechanics/generalized Born surface areaOLS ordinary least squares regressionOPLS optimized potential for liquid simulationsPOPC 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholineQSAR quantitative structure-activity relationshipRMSD root mean square deviationRMSF root mean square fluctuationSA simulated annealingXP extra precision

Association of CYP2C19*2 and ALDH1A1*1/*2 variants with disease outcome in breast cancer patients: results of a global screening array

PurposeCyclophosphamide and doxorubicin (adjuvant chemotherapy) are commonly used to treat breast cancer patients. Variation in the genes involved in pharmacodynamics and pharmacokinetics of these drugs plays an important role in prediction of drug response and survival. The present study was carried out with an aim to evaluate the variation in all the genes involved in pharmacokinetic and pharmacodynamics pathways of cyclophosphamide and doxorubicin, and correlate specific variants with disease outcome in breast cancer patients from the Malwa region of Punjab.MethodsA total of 250 confirmed breast cancer patients were involved in the study. Genotyping was performed on an Illumina Infinium HD assay platform using a Global Screening Array (GSA) microchip. GenomeStudio (Illumina, Inc.) was used for data preprocessing and a p value less than or equal to 5u2009×u200910–8 was considered statistically significant. To rule out the influence of confounding risk factors, a step-wise multivariate regression analysis was carried out to evaluate the association of genotype with overall clinical outcome.ResultsTwo gene variants, CYP2C19 (G681A) and ALDH1A1*2 (17xa0bp deletion), were found to be significantly associated with the disease outcome, including overall survival, recurrence and metastasis, in breast cancer patients on adjuvant therapy. Both these genes are involved in the pharmacokinetics of cyclophosphamide. However, none of the variants in the genes involved in pharmacokinetics and pharmacodynamics of doxorubicin were found to have any significant impact on disease outcome in the studied group.ConclusionCYP2C19 (G681A) variant and ALDH1A1*2 emerged as two important biomarkers associated with bad outcome in breast cancer patients on adjuvant therapy.

Anticancer activity of dihydropyrazolo[1,5-c]quinazolines against rat C6 glioma cells via inhibition of topoisomerase II

The design and synthesis of dihydropyrazolo[1,5‐c]quinazolines (1a–h) as human topoisomerase II (TopoII) catalytic inhibitors are reported. The compounds were investigated for their antiproliferative activity against the C6 rat glial cell line. Two compounds, 1b and 1h, were found to be potent cytotoxic agents against glioma cells and exerted selective TopoII inhibitory activity. Furthermore, the compounds induced alterations in reactive oxygen species levels as measured by DCFDA assay and were found to induce cell cycle arrest at the G1 phase at lower concentrations and profound apoptosis at higher concentrations. The interaction of selected investigational molecules with TopoII was further corroborated by molecular modeling.