Pharmaceutical Sciences and Natural Products - Research Publications

Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56

Browse

Author: search.filters.author.Negi, ArvindHas files: Yes

Search Results

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations
    (Springer Verlag, 2016) Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj
    Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed. ? 2015, Springer-Verlag Berlin Heidelberg.
  • Thumbnail Image
    Item
    Synthesis and xanthine oxidase inhibitory activity of 5,6 dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives
    (Elsevier, 2014) Kumar, Deependra; Kaur, Gagandeep; Negi, Arvind; Kumar, Sanjeev; Singh, Sandeep; Kumar, Raj
    Some 5,6-dihydropyrazolo/pyrazolo[1,5-c]quinazoline derivatives were rationally designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Some notions about structure activity relationships are presented. The compounds 6g, 6h and 6e were found to be significantly active against XO. The compound 6g emerged as the most potent XO inhibitor as compared to allopurinol and free radical scavenger. The molecular docking of 6g into the XO active site highlighted its mode of binding and important interactions such as hydrogen bonding, π–π stacking with amino acid residues like Ser876, Thr1010, Phen914, Phe1009 and Phe649 and its close proximity to dioxothiomolybdenum (MOS).
  • Thumbnail Image
    Item
    Design, microwave-mediated synthesis and biological evaluation of novel 4 aryl(alkyl)amino-3-nitroquinoline and 2,4-diaryl(dialkyl) amino-3-nitroquinolines as anticancer agents
    (Elsevier, 2015) Chauhan, Monika; Rana, Anil; Alex, Jimi Marin; Negi, Arvind; Singh, Sandeep; Kumar, Raj
    Design, microwave-assisted synthesis of novel 4-aryl (alkyl)amino-3-nitroquinoline (1a–1l) and 2,4-diaryl (dialkyl)amino-3-nitroquinolines (2a–2k and 3a) via regioselective and complete nucleophilic substitution of 2,4-dichloro-3-nitroquinoline, respectively in water are presented. The newly synthesized compounds were evaluated for the first time for antiproliferative activity against EGFR overexpressing human lung (A-549 and H-460) and colon (HCT-116-wild type and HCT-116-p53 null) cancer cell lines. Some notions about structure–activity relationships (SAR) are presented. Compounds 2e, 2f, 2j and 3a overall exhibited excellent anticancer activity comparable to erlotinib which was used as a positive control. Molecular modeling studies disclosed the recognition pattern of the compounds and also supported the observed SAR.
  • Thumbnail Image
    Item
    Growth factors mediated cell signalling in prostate cancer progression: Implications in discovery of anti-prostate cancer agents.
    (Elsevier, 2015) Joshi,Gaurav; Singh, Pankaj Kumar; Negi, Arvind; Rana, Anil; Singh, Sandeep; Kumar, Raj
    Cancer is one of the leading causes of mortality amongst world’s population, in which prostate cancer is one of the most encountered malignancies among men. Globally, it is the sixth leading cause of cancer-related death in men. Prostate cancer is more prevalent in the developed world and is increasing at alarming rates in the developing countries. Prostate cancer is mostly a very sluggish progressing disease, caused by the overproduction of steroidal hormones like dihydrotestosterone or due to over-expression of enzymes such as 5-α-reductase. Various studies have revealed that growth factors play a crucial role in the progression of prostate cancer as they act either by directly elevating the level of steroidal hormones or upregulating enzyme efficacy by the active feedback mechanism. Presently, treatment options for prostate cancer include radiotherapy, surgery and chemotherapy. If treatment is done with prevailing traditional chemotherapy; it leads to resistance and development of androgen-independent prostate cancer that further complicates the situation with no cure option left. The current review article is an attempt to cover and establish an understanding of some major signalling pathways intervened through survival factors (IGF-1R), growth factors (TGF-α, EGF), Wnt, Hedgehog, interleukin, cytokinins and death factor receptor which are frequently dysregulated in prostate cancer. This will enable the researchers to design and develop better therapeutic strategies targeting growth factors and their cross talks mediated prostate cancer cell signalling.
  • Thumbnail Image
    Item
    Cystathionine β-Lyase-Like Protein with Pyridoxal Binding Domain Characterized in Leishmania major by Comparative Sequence Analysis and Homology Modelling
    (Hindawi, 2013) Negi, Arvind; Bhushan, Satej; Gupta, Pawan; Garg, Prabha; Kumar, Raj
    Cystathionine β-lyase-like protein (CBLP), one of the key enzymes involved in methionine biosynthesis utilising pyridoxal phosphate (PLP) as a cofactor, has recently been reported in Leishmania major. Its presence in the parasite and absence in humans warrant its full characterisation and fruition as a potent, selective, and inevitable druggable target. Due to the unavailability of X-ray 3D structure of CBLP, a homology model for this protein was developed for the first time. The model was evaluated for PLP binding site and various conserve domain residues of the protein recommended by comparative sequence analyses by different protein analysis tools. The model was validated and discovered to be robust and statistically significant. The final model was superimposed on template of Arabidopsis thaliana (PDB ID: 1IBJ) and RMSD was found to be 0.486. The PLP binding site residues of both the proteins were ensued to be highly conserved indicated by Gly71, Met72, Tyr95, Asp169, and Ser193 as well as formation of aldimine bond with Lys194. This was further verified through molecular simulation of PLP into the cofactor binding site of the modelled protein. The present study may therefore play a directing role in the designing of novel, potential, and selective antileishmanial agents.
  • Thumbnail Image
    Item
    Recent Advancements in Small Molecule Inhibitors of Insulin–like Growth Factor-1 Receptor (IGF-1R) Tyrosine Kinase as Anticancer agents
    (Bentham Science, 2013) Negi, Arvind; Ramarao, P.; Kumar, Raj
    Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer in human, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF- 1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date.