Mohammad Imran Siddiqi

Publications of Mohammad Imran Siddiqi

• β-Amyrin acetate and β-amyrin palmitate as antidyslipidemic agents from Wrightia tomentosa leaves.

  Authors: Ranjani Maurya, Anuj Srivastava, Priyanka Shah, Mohammad Imran Siddiqi, S M Rajendran, Anju Puri, Prem P Yadav

  Phytomedicine : international journal of phytotherapy and phytopharmacology. 04/2012;

  The ethanolic extract and fractions of Wrightia tomentosa Roem. & Schult (Apocynaceae) leaves were tested in vivo for their antidyslipidemic activity in high fat diet (HFD) induced dyslipidemicThe ethanolic extract and fractions of Wrightia tomentosa Roem. & Schult (Apocynaceae) leaves were tested in vivo for their antidyslipidemic activity in high fat diet (HFD) induced dyslipidemic hamsters. Activity guided isolation resulted in identification of antidyslipidemic compounds β-AA and β-AP. Compounds β-AA and β-AP decrease the levels of LDL by 36% and 44%, and increase the HDL-C/TC ratio by 49% and 28%, respectively, at a dose of 10mg/kg. In addition, the isolated compounds β-AA and β-AP showed significant HMG-CoA-reductase inhibition, which was further established by docking studies.

• Insights into structure and function of SHIP2-SH2: homology modeling, docking, and molecular dynamics study.

  Authors: Uzma Saqib, Mohammad Imran Siddiqi

  Journal of chemical biology. 10/2011; 4(4):149-58.

  SRC homology 2 (SH2)-containing inositol 5'-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositolSRC homology 2 (SH2)-containing inositol 5'-phosphatase protein (SHIP2) is a potential target for type 2 diabetes. Its ability to dephosphorylate the lipid messenger phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], important for insulin signaling, makes it an important target against type 2 diabetes. The insulin-induced SHIP2 interaction with Shc is very important for the membrane localization and functioning of SHIP2. There is a bidentate relationship between the two proteins where two domains each from SHIP2 and Shc are involved in mutual binding. However in the present study, the SHIP2-SH2 domain binding with the phosphorylated tyrosine 317 on the collagen-homology (CH) domain of Shc, has been studied due to the indispensability of this interaction in SHIP2 localization. In the absence of the crystal structure of SHIP2-SH2, its structural model was developed followed by tracking its molecular interactions with Shc through molecular docking and dynamics studies. This study revealed much about the structural interactions between the SHIP2-SH2 and Shc-CH. Finally, docking study of a nonpeptide inhibitor into the SHIP2-SH2 domain further confirmed the structural interactions involved in ligand binding and also proposed the inhibitor as a major starting point against SHIP2-SH2 inhibition. The insights gained from the current study should prove useful in the design of more potent inhibitors against type 2 diabetes.

• Discovery of a new class of HMG-CoA reductase inhibitor from Polyalthia longifolia as potential lipid lowering agent.

  Authors: Koneni V Sashidhara, Suriya P Singh, Anuj Srivastava, Anju Puri, Yashpal S Chhonker, Rabi S Bhatta, Priyanka Shah, Mohammad Imran Siddiqi

  European journal of medicinal chemistry. 08/2011; 46(10):5206-11.

  Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1),Bioassay guided fractionation of the ethanolic extract of Polyalthia longifolia var. pendula, led to the discovery of the clerodane diterpene, 16α-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (1), as a new structural class of HMG-CoA reductase inhibitor. Importantly, the in vivo effects of 1 corroborated well with its molecular docking analysis and also with its hamster plasma pharmacokinetics.

• Interaction between sulphur mobilisation proteins SufB and SufC: evidence for an iron-sulphur cluster biogenesis pathway in the apicoplast of Plasmodium falciparum.

  Authors: Bijay Kumar, Sushma Chaubey, Priyanka Shah, Aiman Tanveer, Manish Charan, Mohammad Imran Siddiqi, Saman Habib

  International journal for parasitology. 06/2011; 41(9):991-9.

  The plastid of Plasmodium falciparum, the apicoplast, performs metabolic functions essential to the parasite. Various reactions in the plastid require the assembly of [Fe-S] prosthetic groups onThe plastid of Plasmodium falciparum, the apicoplast, performs metabolic functions essential to the parasite. Various reactions in the plastid require the assembly of [Fe-S] prosthetic groups on participating proteins as well as the reductant activity of ferredoxin that is converted from its apo-form by the assembly of [Fe-S] clusters inside the apicoplast. The [Fe-S] assembly pathway involving sulphur mobilising Suf proteins has been predicted to function in the apicoplast with one component (PfSufB) encoded by the plastid genome itself. We demonstrate the ATPase activity of recombinant P. falciparum nuclear-encoded SufC and its localisation in the apicoplast. Further, an internal region of apicoplast SufB was used to detect PfSufB-PfSufC interaction in vitro; co-elution of SufB from parasite lysate with recombinant PfSufC on an affinity column also indicated an interaction of the two proteins. As a departure from bacterial SufB and similar to reported plant plastid SufB, apicoplast SufB exhibited ATPase activity, suggesting the evolution of specialised functions in the plastid counterparts. Our results provide experimental evidence for an active Suf pathway in the Plasmodium apicoplast.

• Bile acid receptor agonist GW4064 regulates PPARγ coactivator-1α expression through estrogen receptor-related receptor α.

  Authors: Shailendra Kumar Dhar Dwivedi, Nidhi Singh, Rashmi Kumari, Jay Sharan Mishra, Sarita Tripathi, Priyam Banerjee, Priyanka Shah, Vandana Kukshal, Abdul Malik Tyagi, Anil Nilkanth Gaikwad [......] Somali Sanyal, Naibedya Chattopadhyay, Ravishankar Ramachandran, Mohammad Imran Siddiqi, Arun Bandyopadhyay, Ashish Arora, Thomas Lundåsen, Sayee Priyadarshini Anakk, David D Moore, Sabyasachi Sanyal

  Molecular endocrinology (Baltimore, Md.). 06/2011; 25(6):922-32.

  Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeuticPeroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is induced in energy-starved conditions and is a key regulator of energy homeostasis. This makes PGC-1α an attractive therapeutic target for metabolic syndrome and diabetes. In our effort to identify new regulators of PGC-1α expression, we found that GW4064, a widely used synthetic agonist for the nuclear bile acid receptor [farnesoid X receptor (FXR)] strongly enhances PGC-1α promoter reporter activity, mRNA, and protein expression. This induction in PGC-1α concomitantly enhances mitochondrial mass and expression of several PGC-1α target genes involved in mitochondrial function. Using FXR-rich or FXR-nonexpressing cell lines and tissues, we found that this effect of GW4064 is not mediated directly by FXR but occurs via activation of estrogen receptor-related receptor α (ERRα). Cell-based, biochemical and biophysical assays indicate GW4064 as an agonist of ERR proteins. Interestingly, FXR disruption alters GW4064 induction of PGC-1α mRNA in a tissue-dependent manner. Using FXR-null [FXR knockout (FXRKO)] mice, we determined that GW4064 induction of PGC-1α expression is not affected in oxidative soleus muscles of FXRKO mice but is compromised in the FXRKO liver. Mechanistic studies to explain these differences revealed that FXR physically interacts with ERR and protects them from repression by the atypical corepressor, small heterodimer partner in liver. Together, this interplay between ERRα-FXR-PGC-1α and small heterodimer partner offers new insights into the biological functions of ERRα and FXR, thus providing a knowledge base for therapeutics in energy balance-related pathophysiology.

• 2,3-dideoxy hex-2-enopyranosid-4-uloses as promising new anti-tubercular agents: design, synthesis, biological evaluation and SAR studies.

  Authors: Mohammad Saquib, Irfan Husain, Smriti Sharma, Garima Yadav, Vipul K Singh, Sandeep K Sharma, Priyanka Shah, Mohammad Imran Siddiqi, Brijesh Kumar, Jawahar Lal, Girish K Jain, Brahm S Srivastava, Ranjana Srivastava, Arun K Shaw

  European journal of medicinal chemistry. 03/2011; 46(6):2217-23.

  The alarming resurgence of tuberculosis (TB) underlines the urgent need for development of new and potent anti-TB drugs. Towards this goal we herein report the design and synthesis of 2,3-dideoxyThe alarming resurgence of tuberculosis (TB) underlines the urgent need for development of new and potent anti-TB drugs. Towards this goal we herein report the design and synthesis of 2,3-dideoxy hex-2-enopyranosid-4-uloses as promising new anti-tubercular agents. These easily accessible, small molecules were found to exhibit in vitro activity against Mycobacterium tuberculosis H37Rv in a MIC range of 0.78 μg/mL to 25 μg/mL. A detailed SAR study on these hex-2-enopyranosid-4-uloses led to the identification of compound 5g (S007-724) which on the basis of low MIC (0.78 μg/mL-M. tuberculosis H37Rv; 1.56 μg/mL-MDR, SDR strains of M. tuberculosis; 0.78 μg/mL-inhibition of intracellular replication of M. tuberculosis) and SI value of 13.5 has been identified as a promising lead molecule.

• Interaction of apicoplast-encoded elongation factor (EF) EF-Tu with nuclear-encoded EF-Ts mediates translation in the Plasmodiumfalciparum plastid.

  Authors: Subir Biswas, Erin E Lim, Ankit Gupta, Uzma Saqib, Snober S Mir, Mohammad Imran Siddiqi, Stuart A Ralph, Saman Habib

  International journal for parasitology. 03/2011; 41(3-4):417-27.

  Protein translation in the plastid (apicoplast) of Plasmodium spp. is of immense interest as a target for potential anti-malarial drugs. However, the molecular data on apicoplast translation neededProtein translation in the plastid (apicoplast) of Plasmodium spp. is of immense interest as a target for potential anti-malarial drugs. However, the molecular data on apicoplast translation needed for optimisation and development of novel inhibitors is lacking. We report characterisation of two key translation elongation factors in Plasmodium falciparum, apicoplast-encoded elongation factor PfEF-Tu and nuclear-encoded PfEF-Ts. Recombinant PfEF-Tu hydrolysed GTP and interacted with its presumed nuclear-encoded partner PfEF-Ts. The EF-Tu inhibitor kirromycin affected PfEF-Tu activity in vitro, indicating that apicoplast EF-Tu is indeed the target of this drug. The predicted PfEF-Ts leader sequence targeted GFP to the apicoplast, confirming that PfEF-Ts functions in this organelle. Recombinant PfEF-Ts mediated nucleotide exchange on PfEF-Tu and homology modeling of the PfEF-Tu:PfEF-Ts complex revealed PfEF-Ts-induced structural alterations that would expedite GDP release from PfEF-Tu. Our results establish functional interaction between two apicoplast translation factors encoded by genes residing in different cellular compartments and highlight the significance of their sequence/structural differences from bacterial elongation factors in relation to inhibitor activity. These data provide an experimental system to study the effects of novel inhibitors targeting PfEF-Tu and PfEF-Tu.PfEF-Ts interaction. Our finding that apicoplast EF-Tu possesses chaperone-related disulphide reductase activity also provides a rationale for retention of the tufA gene on the plastid genome.

• Alkaline pH-dependent differential unfolding characteristics of mesophilic and thermophilic homologs of dimeric serine hydroxymethyltransferase.

  Authors: Anant Narayan Bhatt, Vinod Bhakuni, Ashutosh Kumar, M Yahiya Khan, Mohammad Imran Siddiqi

  Biochimica et biophysica acta. 02/2010; 1804(6):1294-300.

  Environmental variables such as pH can significantly influence the folding and stability of a protein molecule. In the present investigation, we compared the alkaline pH-induced unfolding of twoEnvironmental variables such as pH can significantly influence the folding and stability of a protein molecule. In the present investigation, we compared the alkaline pH-induced unfolding of two homologous serine hydroxymethyltransferase from mesophilic Bacillus subtilis (bsSHMT) and thermophilic Bacillus stearothermophilus (bstSHMT) using various biophysical techniques. The thermophilic enzyme bstSHMT was found to be more resistant to alkaline denaturation compared to its mesophilic counterpart, bsSHMT. Unfolding studies using domain-swapped chimera, constructed by swapping the C-terminal domain of these two wild-type proteins, revealed that C-terminal domain plays a pivotal role in the folding, stability and subunit interaction of these proteins. Primary amino acid sequence analysis of the proteins showed that bsSHMT has six unconserved lysine residues in C-terminal domain, which are absent in bstSHMT. Chemical modification of lysine side chains resulted in stabilization of monomers, only in case of bsSHMT. Moreover, comparison between homology model of bsSHMT with the crystal structure of bstSHMT revealed that a small stretch of 11 amino acids at the end of C-terminal domain was found protruding outside the molecule as a flexible coiled structure in bsSHMT. Taken together these findings suggest that possibly the presence of these non-identical lysine moieties and a small extension of C-terminal domain may be responsible for low stability of bsSHMT under alkaline pH condition.

• Synthesis and molecular docking studies of 1-phenyl-4-glycosyl-dihydropyridines as potent antileishmanial agents.

  Authors: Vivek Parashar Pandey, Surendra Singh Bisht, Mridul Mishra, Ashutosh Kumar, Mohammad Imran Siddiqi, Aditya Verma, Monika Mittal, Shraddha A Sane, Suman Gupta, Rama P Tripathi

  European journal of medicinal chemistry. 02/2010; 45(6):2381-8.

  A series of 1-phenyl-4-glycosyl-dihydropyridines (4-17 and 19-21) were prepared by the one pot multicomponent reaction of glcosyl aldehyde, beta-keto compounds and aniline or substituted aniline inA series of 1-phenyl-4-glycosyl-dihydropyridines (4-17 and 19-21) were prepared by the one pot multicomponent reaction of glcosyl aldehyde, beta-keto compounds and aniline or substituted aniline in the presence of TBAHS as catalyst. The compounds were screened in vitro and in vivo for their antileishmanial activities. Most of the compounds exhibited moderate to good activity against amastigotes and promastigotes of Leishmania donovani. The compounds 4, 11, 12, 13, and 17 exhibited potent in vivo activity with selectivity index (SI) values 7.43-18.93. Molecular docking studies with these compounds revealed L. donovani PTR1 as the possible target to show antileishmanial activities.

• Characterization of dipeptidylcarboxypeptidase of

  Authors: Mirza Saqib Baig, Ashutosh Kumar, Mohammad Imran Siddiqi, Neena Goyal

  Journal of Computer-Aided Molecular Design. 01/2010; 24:77-87.

• Characterization of dipeptidylcarboxypeptidase of Leishmania donovani: a molecular model for structure based design of antileishmanials.

  Authors: Mirza Saqib Baig, Ashutosh Kumar, Mohammad Imran Siddiqi, Neena Goyal

  Journal of computer-aided molecular design. 01/2010; 24(1):77-87.

  Leishmania donovani dipeptidylcarboxypeptidsae (LdDCP), an angiotensin converting enzyme (ACE) related metallopeptidase has been identified and characterized as a putative drug target forLeishmania donovani dipeptidylcarboxypeptidsae (LdDCP), an angiotensin converting enzyme (ACE) related metallopeptidase has been identified and characterized as a putative drug target for antileishmanial chemotherapy. The kinetic parameters for LdDCP with substrate, Hip-His-Leu were determined as, Km, 4 mM and Vmax, 1.173 micromole/ml/min. Inhibition studies revealed that known ACE inhibitors (captopril and bradykinin potentiating peptide; BPP1) were weak inhibitors for LdDCP as compared to human testicular ACE (htACE) with Ki values of 35.8 nM and 3.9 microM, respectively. Three dimensional model of LdDCP was generated based on crystal structure of Escherichia coli DCP (EcDCP) by means of comparative modeling and assessed using PROSAII, PROCHECK and WHATIF. Captopril docking with htACE, LdDCP and EcDCP and analysis of molecular electrostatic potentials (MEP) suggested that the active site domain of three enzymes has several minor but potentially important structural differences. These differences could be exploited for designing selective inhibitor of LdDCP thereby antileishmanial compounds either by denovo drug design or virtual screening of small molecule databases.

• New molecular scaffolds for the design of Mycobacterium tuberculosis type II dehydroquinase inhibitors identified using ligand and receptor based virtual screening.

  Authors: Ashutosh Kumar, Mohammad Imran Siddiqi, Stanislav Miertus

  Journal of molecular modeling. 10/2009;

  Using ligand and receptor based virtual screening approaches we have identified potential virtual screening hits targeting type II dehydroquinase from Mycobacterium tuberculosis, an effective andUsing ligand and receptor based virtual screening approaches we have identified potential virtual screening hits targeting type II dehydroquinase from Mycobacterium tuberculosis, an effective and validated anti-mycobacterial target. Initially, we applied a virtual screening workflow based on a combination of 2D structural fingerprints, 3D pharmacophore and molecular docking to identify compounds that rigidly match specific aspects of ligand bioactive conformation. Subsequently, the resulting compounds were ranked and prioritized using receptor interaction fingerprint based scoring and quantitative structure activity relationship model developed using already known actives. The virtual screening hits prioritized belong to several classes of molecular scaffolds with several available substitution positions that could allow chemical modification to enhance binding affinity. Finally, identified hits may be useful to a medicinal chemist or combinatorial chemist to pick up the new molecular starting points for medicinal chemistry optimization for the design of novel type II dehydroquinase inhibitors.

• Knowledge Based Identification of Potent Antitubercular Compounds Using Structure Based Virtual Screening and Structure Interaction Fingerprints.

  Authors: Ashutosh Kumar, Vinita Chaturvedi, Shalini Bhatnagar, Sudhir Sinha, Mohammad Imran Siddiqi

  Journal of chemical information and modeling. 01/2009;

  In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antitubercular agents with novel structures. Thymidine monophosphate kinaseIn view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antitubercular agents with novel structures. Thymidine monophosphate kinase from M. tuberculosis (TMPKmt) is an attractive target for antitubercular chemotherapy. We report here the identification of potent antitubercular compounds targeting TMPKmt using virtual screening methods. For this purpose we have developed a pharmacophore hypothesis based on the substrate and known TMPKmt inhibitors and employed it to screen the Maybridge small molecule database. The molecular docking was then performed in order to select the compounds on the basis of their ability to form favorable interactions with the TMPKmt active site. In addition, we applied straightforward weighting using structure interaction fingerprints to include additional knowledge into structure based virtual screening. Eight compounds were acquired and evaluated for antitubercular activity against M. tuberculosis H37Rv in vitro, and out of these 3 compounds showed MIC of 3.12 mug/mL whereas 2 compounds showed MIC of 12.5 mug/mL. All the active compounds were found to be nontoxic in Vero cell lines and mice bone marrow macrophages. All the identified hits highlighted a key hydrogen bonding interaction with Arg74. The observed pi-stacking interaction with Phe70 was also produced by the identified hits. These hits represent promising starting points for structural optimization in hit-to-lead development.

• 3D-QSAR studies of xanthone derivatives as human alpha glucosidase inhibitors

  Authors: Saqib Uzma, Mohammad Imran Siddiqi

  International Journal of Integrative Biology. 01/2009;

  Three-dimensional quantitative structure activity relationship (3D-QSAR) analyses were carried out on a set of 42 xanthone derivatives in order to understand their anti-alpha glucosidic activities.Three-dimensional quantitative structure activity relationship (3D-QSAR) analyses were carried out on a set of 42 xanthone derivatives in order to understand their anti-alpha glucosidic activities. The studies include Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Models with good predictive abilities were generated with the cross validated r2 (r2cv) values for CoMFA and CoMSIA being 0.580 and 0.610 respectively. The conventional r2 values were 0.949 each for both CoMFA and CoMSIA models. In addition, a homology model of human alpha glucosidase was used for docking based alignment of the compounds. The most active compound then served as a template for the alignment of the remaining structures in order to align all compounds prior to QSAR studies. Further, mapping of contours onto the active site validated each other in terms of residues involved with reference to respective contours. This integrated molecular docking based alignment followed by 3D-QSAR studies should provide further insights to support structure-based design of anti-diabetic agents with improved activity profiles.

• Virtual screening against Mycobacterium tuberculosis dihydrofolate reductase: Suggested workflow for compound prioritization using structure interaction fingerprints.

  Authors: Ashutosh Kumar, Mohammad Imran Siddiqi

  Journal of molecular graphics & modelling. 09/2008;

  In this study, we suggest a new workflow for the identification and prioritization of potential compounds targeted against Mycobacterium tuberculosis dihydrofolate reductase, an important folateIn this study, we suggest a new workflow for the identification and prioritization of potential compounds targeted against Mycobacterium tuberculosis dihydrofolate reductase, an important folate cycle enzyme and a validated target for the development of anti-tubercular agents. First, we have performed an integrated pharmacophore and structure-based virtual screening using Maybridge small molecule database, subsequently interaction patterns from known actives to the receptor were applied for scoring and ranking the virtual screening hits using structure interaction fingerprint (SIFt)-based similarity approach. In addition, agglomerative hierarchical clustering of the structure interaction fingerprints permits the easy separation of active from inactive binding modes. Using this approach we screened 59275 Maybridge compounds and 20 compounds were prioritized as promising virtual screening hits. Though using a receptor interaction scoring approach, the results were not biased toward the chemical classes of the known actives and the proposed compounds were structurally diverse with low molecular weights and structural complexities. Our results suggest that structure-based virtual screening coupled with the SIFt should be a valuable tool for prioritization of virtual screening hits.

• Molecular cloning and characterization of Plasmodium falciparum transketolase.

  Authors: Shweta Joshi, Alok Ranjan Singh, Ashutosh Kumar, Prakash Chandra Misra, Mohammad Imran Siddiqi, Jitendra Kumar Saxena

  Molecular and biochemical parasitology. 08/2008; 160(1):32-41.

  The pentose phosphate pathway (PPP) is an important metabolic pathway for yielding reducing power in the form of NADPH and production of pentose sugar needed for nucleic acid synthesis.The pentose phosphate pathway (PPP) is an important metabolic pathway for yielding reducing power in the form of NADPH and production of pentose sugar needed for nucleic acid synthesis. Transketolase, the key enzyme of non-oxidative arm of PPP, plays a vital role in the survival/replication of the malarial parasite. This enzyme in Plasmodium falciparum is a novel drug target as it has least homology with the human host. In the present study, the P. falciparum transketolase (PfTk) was expressed, localized and biochemically characterized. The recombinant PfTk harboring transketolase activity catalyzed the oxidation of donor substrates, fructose-6-phosphate (F6P) and hydroxypyruvate (HP), with K(m)(app) values of 2.25 and 4.78 mM, respectively. p-Hydroxyphenylpyruvate (HPP) was a potent inhibitor of PfTk, when hydroxypyruvate was used as a substrate, exhibiting a K(i) value of 305 microM. At the same time, noncompetitive inhibition was observed with F6P. The native PfTk is a hexamer with subunit molecular weight of 70kDa, which on treatment with low concentrations of guanidine hydrochloride (GdmCl) dissociated into functionally active dimers. This protein was localized in the cytosol and nucleus of the parasite as studied by confocal microscopy. A model structure of PfTk was constructed based on the crystal structure of the transketolases of Saccharomyces cerevisae, Leishmania mexicana and Escherichia coli to assess the structural homology. Consistent with the homology modeling predictions, CD analysis indicated that PfTk is composed of 39% alpha-helices and 26% beta-sheets. The availability of a structural model of PfTk and the observed differences in its kinetic properties compared to the host enzyme may facilitate designing of novel inhibitors of PfTk with potential anti-malarial activity.

• An unconventional form of actin in protozoan haemoflagellate, Leishmania.

  Authors: Prabodh Kapoor, Amogh A Saharabuddhe, Ashutosh Kumar, Kalyan Mitra, Mohammad Imran Siddiqi, Chhitar M Gupta

  The Journal of biological chemistry. 07/2008;

  Leishmania actin was cloned, over expressed in baculovirus-insect cell system and purified to homogeneity. The purified protein polymerized optimally in the presence of Mg2+ and ATP, but differedLeishmania actin was cloned, over expressed in baculovirus-insect cell system and purified to homogeneity. The purified protein polymerized optimally in the presence of Mg2+ and ATP, but differed from conventional actins in its following properties: (i) it did not polymerize in the presence of Mg2+ alone, (ii) it polymerized in a restricted range of pH 7.0-8.5, (iii) its critical concentration for polymerization was found to be 3-4 fold lower than of muscle actin, (iv) it predominantly formed bundles rather than single filaments at pH 8.0, (v) it displayed considerably higher ATPase activity during polymerization, (vi) it did not inhibit DNase-I activity, and (vii) it did not bind the F-actin-binding toxin phalloidin or the actin polymerization disrupting agent Latrunculin B. Computational and molecular modeling studies revealed that the observed unconventional behaviour of Leishmania actin is related to the diverged amino acid stretches in its sequence, which may lead to changes in the overall charge distribution on its solvent exposed surface, ATP binding cleft, Mg2+ binding sites, and the hydrophobic loop which is involved in monomer-monomer interactions. Phylogenetically, it is related to ciliate actins, but to the best of our knowledge, no other actin with such unconventional properties has been reported to date. It is therefore suggested that actin in Leishmania may serve as a novel target for design of new antileishmanial drugs.

• Leishmania donovani pteridine reductase 1: Biochemical properties and structure-modeling studies.

  Authors: Pranav Kumar, Ashutosh Kumar, Shyam Sundar Verma, Namrata Dwivedi, Nasib Singh, Mohammad Imran Siddiqi, Rama Pati Tripathi, Anuradha Dube, Neeloo Singh

  Experimental parasitology. 07/2008;

  Pteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolicPteridine reductase 1 (PTR1, EC 1.5.1.33) is a NADPH dependent short-chain reductase (SDR) responsible for the salvage of pterins in the protozoan parasite Leishmania. This enzyme acts as a metabolic bypass for drugs targeting dihydrofolate reductase, therefore, for successful antifolate chemotherapy to be developed against Leishmania, it must target both enzyme activities. Based on homology model drawn on recombinant pteridine reductase isolated from a clinical isolate of L. donovani, we carried out molecular modeling and docking studies with two compounds of dihydrofolate reductase specificity showing promising antileishmanial activity in vitro. Both the inhibitors appeared to fit well in the active pocket revealing the tight binding of the carboxylic acid ethyl ester group of pyridine moiety to pteridine reductase and identify the important interactions necessary to assist the structure based development of novel pteridine reductase inhibitors.

• Synthesis, molecular docking and PTP1B inhibitory activity of functionalized 4,5-dihydronaphthofurans and dibenzofurans.

  Authors: Manish Dixit, Uzma Saeed, Amit Kumar, Mohammad Imran Siddiqi, Akhilesh K Tamrakar, Arvind K Srivastava, Atul Goel

  Medicinal chemistry (Shāriqah (United Arab Emirates)). 02/2008; 4(1):18-24.

  Protein tyrosine phosphatase 1B (PTP1B) is an enzyme that plays a critical role in down-regulating insulin signaling through dephosphorylation of the insulin receptor. Inhibitors of PTP1B showedProtein tyrosine phosphatase 1B (PTP1B) is an enzyme that plays a critical role in down-regulating insulin signaling through dephosphorylation of the insulin receptor. Inhibitors of PTP1B showed increased insulin sensitivity and normalize plasma glucose level and thus are useful therapeutic agents for the treatment of diabetes. A series of functionalized 4,5-dihydronaphthofurans and dibenzofurans were synthesized, studied through molecular docking and evaluated for their PTP1B inhibitory activity.

• Molecular docking studies on DMDP derivatives as human DHFR inhibitors.

  Authors: Vivek Srivastava, Ashutosh Kumar, Bhartendu Nath Mishra, Mohammad Imran Siddiqi

  Bioinformation. 02/2008; 3(4):180-8.

  Molecular docking is routinely used for understanding drug-receptor interaction in modern drug design. Here, we describe the docking of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives asMolecular docking is routinely used for understanding drug-receptor interaction in modern drug design. Here, we describe the docking of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as inhibitors to human dihydrofolate reductase (DHFR). We docked 78 DMDP derivates collected from literature to DHFR and studied their specific interactions with DHFR. A new shape-based method, LigandFit, was used for docking DMDP derivatives into DHFR active sites. The result indicates that the molecular docking approach is reliable and produces a good correlation coefficient (r(2) = 0.499) for the 73 compounds between docking score and IC(50) values (Inhibitory Activity). The chloro substituted naphthyl ring of compound 63 makes significant hydrophobic contact with Leu 22, Phe 31 and Pro 61 of the DHFR active site leading to enhanced inhibition of the enzyme. The docked complexes provide better insights to design more potent DHFR inhibitors prior to their synthesis.