Pharmaceutical Sciences and Natural Products - Research Publications

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

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Author: search.filters.author.Kalra, SouravSubject: search.filters.subject.Cancer

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    Flavonoids as P-glycoprotein inhibitors for multidrug resistance in cancer: an in-silico approach
    (Taylor and Francis Ltd., 2022-09-19T00:00:00) Kumar, Amit; Kalra, Sourav; Jangid, Kailash; Jaitak, Vikas
    Cancer has become a leading cause of mortality due to non-communicable diseases after cardiovascular disease worldwide and is increasing day by day at a daunting pace. According to an estimate by 2040 there will be 28.4 million cancer cases. Occurrence of multidrug resistance has further worsened the scenario of available cancer treatment. Among different mechanisms of multidrug resistance efflux of xenobiotics by ABC transporter is of prime importance. P-glycoprotein (P-gp) is the major factor behind occurrence of multidrug resistance due to its wide distribution and invariably big binding cavity. Various generations of chemical inhibitors for P-gp have been designed and tested are not devoid of major side effects. Thus, in present study flavonoids a major class of natural compounds was virtually screened in order to find molecules which can be used as selective P-gp inhibitors to be used along with chemotherapeutics. After screening 4275 molecules from different classes of flavonoids i.e. flavan, flavanol, flavonone, flavone, anthocyanins, and isoflavone, through Glide docking top ten hit molecules were selected based on their binding affinity, binding energy calculation and pharmacokinetic properties. All the hit molecules were found to have docking score within the range of ?11.202 to ?9.699 kcal/mol showing very strong interaction with the amino acid residues of binding pocket. Whereas, dock score of standard P-gp inhibitor verapamil was ?4.984 kcal/mol. The ligand and protein complex were found to be quite stable while run through molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Rationalization of the activity Profile of Pyruvate Kinase Isozyme M2 (PKM2) Inhibitors using 3D QSAR
    (Bentham Science Publishers, 2021-08-05T00:00:00) Kusuma, Merugumala; Arora, Sahil; Kalra, Sourav; Chaturvedi, Anuhar; Heuser, Michael; Kumar, Raj
    Introduction: Pyruvate kinase isozyme M2 (PKM2) was observed to be overexpressed and play a key role in cell growth and cancer cells' metabolism. During the past years, phytochemicals have been developed as new treatment options for chemoprevention and cancer therapy. Natural re-sources, like shikonin (naphthoquinone) and its derivatives, have emerged to be high potential therapeutics in cancer treatment. Methods: Our study aimed to design novel anti-tumour agents (PKM2 inhibitors) focusing on the shikonin scaffold with a better activity using computational methods. We applied a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using Field-based QSAR. Results: The Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of forty shikonin derivatives, including shikonin, to develop robust models and rationalize the PKM2 inhibitory activity profile by building a correlation between structural features and activity. Conclusion: These predictive computational models will further help the design and synthesis of potent PKM2 inhibitors and their fast biological assessment at a low cost. � 2021 Bentham Science Publishers.