Browsing by Author "Mohammad Kashif"

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Aqua-(2-formylbenzoato)triphenyltin(IV) induces cell cycle arrest and apoptosis in hypoxic triple negative breast cancer cells
(Elsevier Ltd, 2023) Virendra Singh; Nishant Kumar Rana; Mohammad Kashif; Partha Pratim Manna; Tushar S. Basu Baul; Biplob Koch
Hypoxia plays a vital role in tumor microenvironment by allowing development and maintenance of cancer cells thereby led to major hindrance for effective anticancer therapy and main reason for failure of most anticancer drugs. We herein investigated the therapeutic efficacy and molecular mechanism of action of aqua-(2-formylbenzoato) triphenyltin (IV) compound (OTC) in MDA-MB-231 cell line. Cobalt chloride induced hypoxic MDA-MB-231 cells treated with OTC were used to access cytotoxicity, ROS, cellular apoptosis, and cell cycle progression. Further, expression of HIF-1α and VEGF, as well as apoptotic proteins like p53, Bax, Bcl-2 and caspase 3 were assessed. The findings indicated that OTC is more effective towards CoCl2 induced hypoxic cells when compared to normoxic cells and the results are far superior to doxorubicin. Additionally, our study revealed that OTC facilitates more ROS production induced cell cycle arrest and promote apoptosis. Furthermore, OTC significantly down regulates the expression of Hif-1α, VEGF and Bcl-2 in hypoxic condition and elevates the level of p53, Bax, cytochrome-C and Caspase 3. Our in vitro studies demonstrated that OTC showed better efficacy than doxorubicin, corroborating that OTC could be a promising compound for hypoxic cancer that also display multi drug resistant. © 2022 Elsevier Ltd
Identification of novel inhibitors against UDP-galactopyranose mutase to combat leishmaniasis
(Wiley-Liss Inc., 2018) Mohammad Kashif; Shams Tabrez; Atahar Husein; Mohd Arish; Ponnusamy Kalaiarasan; Partha P. Manna; Naidu Subbarao; Yusuf Akhter; Abdur Rub
Leishmania, a protozoan parasite that causes leishmaniasis, affects 1-2 million people every year worldwide. Leishmaniasis is a vector born disease and characterized by a diverse group of clinical syndromes. Current treatment is limited because of drug resistance, high cost, poor safety, and low efficacy. The urgent need for potent agents against Leishmania has led to significant advances in the development of novel antileishmanial drugs. β-galactofuranose (β-Galf) is an important component of Leishmanial cell surface matrix and plays a critical role in the pathogenesis of parasite. UDP-galactopyranose mutase (UGM) converts UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf) which acts as the precursor for β-Galf synthesis. Due to its absence in human, this enzyme is selected as the potential target in search of new antileishmanial drugs. Three dimensional protein structure model of Leishmania major UGM (LmUGM) has been homology modeled using Trypanosoma cruzi UGM (TcUGM) as a template. The stereochemistry was validated further. We selected already reported active compounds from PubChem database to target the LmUGM. Three compounds (6064500, 44570814, and 6158954) among the top hit occupied the UDP binding site of UGM suggested to work as a possible inhibitor for it. In vitro antileishmanial activity assay was performed with the top ranked inhibitor, 6064500. The 6064500 molecule has inhibited the growth of Leishmania donovani promastigotes significantly. Further, at similar concentrations it has exhibited significantly lesser toxicity than standard drug miltefosine hydrate in mammalian cells. © 2017 Wiley Periodicals, Inc.
Immunoinformatics based design and prediction of proteome-wide killer cell epitopes of Leishmania donovani: Potential application in vaccine development
(Taylor and Francis Ltd., 2022) Mohammad Kashif; Sumit Kumar Hira; Partha Pratim Manna
Despite several extensive and exhaustive efforts, search for potential therapy against leishmaniasis has not made much progress. In the present work, we have employed mining strategy to screen Leishmania donovani proteome for identification of promising vaccine candidate. We have screened 21 potential antigenic proteins from 7960 total protein of L. donovani, based on the presence of signal peptide, GPI anchor, antigenicity prediction and substractive proteomic approach. Secondly, we have also performed comprehensive immunogenic epitope prediction from the screened 21 proteins, using IEDB-AR tools. Out of the 21 antigenic proteins, we obtained 11 immunogenic epitopes from 9 proteins. The final results revealed that four predicted epitopes namely; YPAFAALVF, VAVAATVAY, AAAPTEAAL and MYPLVAVVF, have significantly better binding potential with respective alleles and could elicits immune responses. Docking analysis using PATCHDOCK server and molecular dynamic simulation using GROMACS revealed the potential of the sequences as immunogenic epitopes. In silico studies also suggested that the epitopes occupied almost same binding cleft with the respective alleles, when compared with the reference peptides. It is also suggested from the molecular dynamic simulation data that the peptides were intact in the pocket for longer periods of time. Our study was designed to select MHC class I restricted epitopes for the activation of CD8 T cells using immunoinformatics for the prediction of probable vaccine candidate against L. donovani parasites. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
In silico studies and evaluation of antiparasitic role of a novel pyruvate phosphate dikinase inhibitor in Leishmania donovani infected macrophages
(Elsevier B.V., 2019) Mohammad Kashif; Sumit Kumar Hira; Anurag Upadhyaya; Uttam Gupta; Ranjeet Singh; Ankush Paladhi; Faez Iqbal Khan; Abdur Rub; Partha Pratim Manna
The present work deals with the identification and characterization of a novel inhibitor Z220582104, specific to pyruvate phosphate dikinase, for leishmanicidal activities against free promastigotes and intracellular amastigotes. We have used structure-based drug designing approaches and performed homology modelling, virtual screening and molecular dynamics studies. Primary mouse macrophages and macrophage cell line J774A1 were infected with promastigotes of Leishmania donovani. Both promastigotes and infected macrophages were subjected to treatment with the varying concentrations of Z220582104 or miltefosine for assessment of leishmanicidal activity. The novel inhibitor Z220582104 demonstrated growth inhibitory potential and reduced the viability of the free promastigotes in a concentration- and time-dependent manner. Z220582104 was also effective against the intracellular form of the parasites and reduced the number of amastigotes in macrophages and also lowered the parasite index, compared with the untreated infected macrophages. Although less effective compared with the miltefosine, Z220582104 is well tolerated by the dividing cells and normal human lymphocytes and monocytes with no adverse effects on the growth kinetics or viability. Our in silico and in vitro studies suggested that Leishmania donovani pyruvate phosphate dikinase could be a potential new drug target. © 2018 Elsevier B.V. and International Society of Chemotherapy
Leishmanicidal activity of an in Silico-screened novel inhibitor against ascorbate peroxidase of leishmania donovani
(American Society for Microbiology, 2020) Mohammad Kashif; Ankush Paladhi; Ranjeet Singh; Sankar Bhattacharyya; Sumit Kumar Hira; Partha Pratim Manna
Peroxidases are a heterogeneous family of enzymes that have diverse biological functions. Ascorbate peroxidase is a redox enzyme that is reduced by trypanothione, which plays a central role in the redox defense system of Leishmania. In view of developing new and novel therapeutics, we performed in silico studies in order to search for a ligand library and identify new drug candidates and their physiological roles against promastigotes and intracellular amastigotes of Leishmania donovani. Our results demonstrated that the selected inhibitor ZINC96021026 has significant antileishmanial effect and effectively killed both free and intracellular forms of the parasite. ZINC96021026 was found to be identical to ML-240, a selective inhibitor of valosin-containing protein (VCP), or p97, a member of the AAA-ATPase protein family which was derived from the scaffold of N2,N4-dibenzylquinazoline-2,4-diamine (DBeQ), targeting the D2-ATPase domain of the enzyme. ZINC96021026 (ML-240) thus has a broad range of cellular functions, thought to be derived from its ability to unfold proteins or disassemble protein complexes, besides inhibiting the ascorbate peroxidase activity. ML-240 may inhibit the parasite's ascorbate peroxidase, leading to extensive apoptosis and inducing generation of reactive oxygen species. Taken together, our results demonstrated that ML-240 could be an attractive therapeutic option for treatment against leishmaniasis. © 2020 American Society for Microbiology. All rights reserved.
Recent Advances in Chemotherapeutics for Leishmaniasis: Importance of the Cellular Biochemistry of the Parasite and Its Molecular Interaction with the Host
(MDPI, 2023) Ranjeet Singh; Mohammad Kashif; Prateek Srivastava; Partha Pratim Manna
Leishmaniasis, a category 1 neglected protozoan disease caused by a kinetoplastid pathogen called Leishmania, is transmitted through dipteran insect vectors (phlebotomine, sand flies) in three main clinical forms: fatal visceral leishmaniasis, self-healing cutaneous leishmaniasis, and mucocutaneous leishmaniasis. Generic pentavalent antimonials have long been the drug of choice against leishmaniasis; however, their success is plagued with limitations such as drug resistance and severe side effects, which makes them redundant as frontline therapy for endemic visceral leishmaniasis. Alternative therapeutic regimens based on amphotericin B, miltefosine, and paromomycin have also been approved. Due to the unavailability of human vaccines, first-line chemotherapies such as pentavalent antimonials, pentamidine, and amphotericin B are the only options to treat infected individuals. The higher toxicity, adverse effects, and perceived cost of these pharmaceutics, coupled with the emergence of parasite resistance and disease relapse, makes it urgent to identify new, rationalized drug targets for the improvement in disease management and palliative care for patients. This has become an emergent need and more relevant due to the lack of information on validated molecular resistance markers for the monitoring and surveillance of changes in drug sensitivity and resistance. The present study reviewed the recent advances in chemotherapeutic regimens by targeting novel drugs using several strategies including bioinformatics to gain new insight into leishmaniasis. Leishmania has unique enzymes and biochemical pathways that are distinct from those of its mammalian hosts. In light of the limited number of available antileishmanial drugs, the identification of novel drug targets and studying the molecular and cellular aspects of these drugs in the parasite and its host is critical to design specific inhibitors targeting and controlling the parasite. The biochemical characterization of unique Leishmania-specific enzymes can be used as tools to read through possible drug targets. In this review, we discuss relevant metabolic pathways and novel drugs that are unique, essential, and linked to the survival of the parasite based on bioinformatics and cellular and biochemical analyses. © 2023 by the authors.
Screening of novel inhibitors against Leishmania donovani calcium ion channel to fight leishmaniasis
(Bentham Science Publishers B.V., 2017) Mohammad Kashif; Partha P. Manna; Yusuf Akhter; Mohammed Alaidarous; Abdur Rub
Leishmania is an intracellular protozoan parasite which causes Leishmaniasis, a global health problem affecting millions of people throughout 89 different countries in the world. The current treatment which includes use of amphotericin B, antimonials, and others has major drawbacks due to toxicity, resistance, and extraordinary high cost. So there is an urgent need of development of new drug targets to fight against leishmaniasis. In this regard we have selected Leishmania donovani Ca2+ ion channel (Ld-CC) as potential drug target. Ld-CC regulates concentration of Ca2+ ions which is involved in several functions like flagellar motion, mitochondrial oxidative metabolism and entry inside the macrophages. Since Ld-CC has not been characterised yet, we performed homology modelling of Leishmania donovani Ca2+ ion channel (Ld-CC) and docking studies of ligand library against this channel. 542 compound library of National Cancer Institute (NCI) diversity 3 dataset selected for screening studies. The ligands ZINC17287336 and ZINC29590262 were selected as best energy conformers because they show highest binding affinity towards its target (Ld-CC). They interact with the active site residues in the pocket of Ld-CC which suggests that the docked conformations are good and acceptable. Moreover, these two selected compounds also have relatively high binding affinity than nifedipine and verapamil, known human calcium channel blockers which had been reported to have mild anti-leishmanial activity. Among these two top screened inhibitors the ligand ZINC29590262 shows poor binding affinity towards the Human voltage-dependent L-type calcium channel subunit alpha-1C in comparison to the Ld-CC. Therefore, we proposed this ligand as the best inhibitor which shows 40% more binding affinity with Ld-CC than the human-VDCC. These results suggest that our screened ligand ZINC29590262 could act as novel drug and may show much better antileishmanial activity. © 2017 Bentham Science Publishers.
Synthesis, Biological Evaluation, Molecular Docking and DFT Study of Potent Antileishmanial Agents Based on the Thiazolo[3, 2-a]pyrimidine Chemical Scaffold
(Wiley-Blackwell, 2018) Radha N. Chaturvedi; Mohd Arish; Mohammad Kashif; Varinder Kumar; Reenu; Krishnaiah Pendem; Abdur Rub; Sunita Malhotra
A series of 20 compounds having thiazolo[3, 2-a]pyrimidine chemical scaffold were synthesized and evaluated for their antileishmanial activity against promastigotes of Leishmania donovani. Amongst all, two compounds showed promising antileishmanial activity in comparison to other compounds. Inhibitory concentration 50% (IC50) was calculated as 42.1 μM and 25.1 μM with selectivity index of 8.3 and 6.05, respectively against Miltefosine (reference drug) 37.78 μM with selectivity index of 2.05. To confirm the target of the these molecules, we modelled Leishmania donovani Ca2+ ion channel (LdCC) protein and performed the docking analysis of the best antileishmanial activity exhibiting inhibitors. The free energy of binding was observed as −10.2 and −9.6 kcal mol−1 in comparison to reference drug −6.2 kcal mol−1. It also makes several hydrogen bonds with our conserved residue Ser1655, Tyr1598 and Asn927. Furthermore, several hydrophobic contacts were also observed within the pocket. Finally, computational work employing density functional theory (DFT) was also carried out to investigate the electronic properties of the synthesized compounds. The in vitro and in silico activities conclusively revealed that our lead compounds may be used as a novel therapeutics against leishmaniasis. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Synthesis, crystal structure, Hirshfeld surface analysis, DFT investigation, and molecular docking, of novel organic dithiocarbamates obtained from Baylis-Hillman adducts/alcohols at room temperature
(Elsevier B.V., 2024) Vishal Prasad Sharma; Vipin Kumar; Rashmi Singh; Priyanka Sonker; Priyanka Yadav; Mohammad Kashif; Archana Gaurav; Ashish Kumar Tewari
Several new organic dithiocarbamates were produced in aqueous ethanol using a one-pot multicomponent reaction involving Baylis-Hillman adducts/alcohols, CS2, and different secondary amines. Because of the short reaction periods and high yields, this approach is easy, green, and cost-effective for producing biologically relevant dithiocarbamates at room temperature. The structure of the synthesized dithiocarbamates was confirmed using 1H, 13C NMR, HRMS, and single-crystal X-ray diffraction methods. The HOMO–LUMO energy gap, Mulliken charges, and MESPs have all been computed and presented. Hirshfeld surface analysis and accompanying two-dimensional fingerprint plots, as well as compound interaction energy estimates, were employed as theoretical methodologies to examine the driving force for crystal structure development via intermolecular interactions in their crystal lattices. A molecular docking study was also performed to evaluate the probable interactions and binding manner of the newly synthesized compounds (4a-4w) to the E. coli nitroreductase enzyme. The docking analysis suggested that the compounds (4k, 4g, 4l, and 4m) may inhibit the activity of the nitroreductase enzyme of E. coli. © 2024 Elsevier B.V.
Telomerase Responsive Delivery of Doxorubicin from Mesoporous Silica Nanoparticles in Multiple Malignancies: Therapeutic Efficacies against Experimental Aggressive Murine Lymphoma
(American Chemical Society, 2018) Prateek Srivastava; Sumit Kumar Hira; Amod Sharma; Mohammad Kashif; Prashant Srivastava; Divesh Narayan Srivastava; Ram Adhar Singh; Partha Pratim Manna
Mammalian telomerase maintains the length and integrity of telomeres by adding the telomeric repeats to the chromosome end. This work describes the telomerase responsive delivery of doxorubicin against telomerase positive human and murine cancer cells. Wrapping of doxorubicin loaded mesoporous silica nanoparticles with specific oligonucleotide sequence, containing telomeric repeat complementary sequence and a telomerase substrate primer sequence, resulted in slow and sustained release of doxorubicin, contiguous to the tumor cells. The DNA wrapped nanoprobe significantly inhibits the proliferation and enhanced the cytotoxicity in telomerase positive human and mouse tumor cells, and its function is impeded following exposure to specific telomerase inhibitor, AZT. Entrapping of doxorubicin by telomerase specific oligo manifests enhanced apoptosis and significantly higher uptake of the drug in the tumor cells. Treatment of telomerase positive Dalton's lymphoma bearing mice with a novel and newly designed oligo wrapped nanoprobe, specific for mouse telomerase, significantly enhanced the survival and improved the histopathological parameters. In addition, the treatment also induced significant reduction in the number of tumor foci and restored the normal architecture of the vascularized organs, besides preventing metastasis. © 2018 American Chemical Society.