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Papers by Akbar Ali

Journal of Pharmaceutical Research International

Introduction: E coli is one of the most important etiologic agent of diarrhea in children and adu... more Introduction: E coli is one of the most important etiologic agent of diarrhea in children and adults. Based on the clinical features and virulence determinants, there are five major E. coli strains which cause diarrhea; Enterohemorrhagic E. coli (EHEC), Enteropathogenic E. coli (EPEC), Enterotoxigenic E. coli (ETEC), Enteroinvasive E. coli (EIEC) and Enteroaggregative E. coli (EAEC). The PCR based identification proves to be a better choice as it can differentiate between different strains on the basis of genetic difference. Aim: The purpose of the current study was to isolate diarrheagenic E. coli from the drinking and wastewater from Rafha city of Saudi Arabia. Methodology: One 100 drinking and wastewater samples (50 each) were included in the study. The samples were cultured on MacConkey agar plates at 37 oC for 24 hours. Pink colonies were carefully picked and subjected to DNA isolation and PCR detection and identification of E. coli and Diarrheagenic E. coli. The detected PCR p...

International Journal of Applied and Computational Mathematics, 2016

Continuing the recent work of L. Zhong and K. Xu [MATCH Commun. Math. Comput. Chem. 71 (2014) 627... more Continuing the recent work of L. Zhong and K. Xu [MATCH Commun. Math. Comput. Chem. 71 (2014) 627-642], we determine inequalities among several vertex-degree-based topological indices; first geometric-arithmetic index (GA), augmented Zagreb index (AZI), Randić index (R), atom-bond connectivity index (ABC), sum-connectivity index (X) and harmonic index (H).

Chemical communications (Cambridge, England), Jan 14, 2014

A simple and efficient metal-free methodology for the regioselective synthesis of 1,4-disubstitut... more A simple and efficient metal-free methodology for the regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles has been developed by applying a novel inverse electron-demand-1,3-dipolar cycloaddition approach. The practical one-pot metal-free strategy can be accomplished with various alkylidene malononitriles and aromatic azides in the presence of base.

Journal of Radioanalytical and Nuclear Chemistry, 2011

Journal of Radioanalytical and Nuclear Chemistry, 2012

Journal of Medicinal Chemistry, 2006

Journal of Medicinal Chemistry, 2009

Chemistry & Biology, 2013

Biochemistry, 1981

ABSTRACT

Journal of Radioanalytical and Nuclear Chemistry Articles, 1996

... 3, The Chemical Processing of Irradiated Fuels from Thermal Reactors, Pergamon Press, 1961, p... more ... 3, The Chemical Processing of Irradiated Fuels from Thermal Reactors, Pergamon Press, 1961, p. 151. 4. TS LAXMINARAYAN, SK PATIL, HD SHARMA, J. lnorg. Nucl. ... 13. SR MOHANTY, ASREDDY, J. Inorg. Nucl. ... 15. MH KHAN, SM HASANY, MA KHAN, A. ALl, J. Radioanal. ...

ACS Chemical Biology, 2015

This study examines the specificity and mechanism of action of a recently reported hepatitis C vi... more This study examines the specificity and mechanism of action of a recently reported hepatitis C virus (HCV) non-structural protein 3 (NS3) helicase-protease inhibitor (HPI), and the interaction of HPI with the NS3 protease inhibitors telaprevir, boceprevir, danoprevir, and grazoprevir. HPI most effectively reduced cellular levels of subgenomic genotype 4a replicons, followed by genotypes 3a and 1b replicons. HPI had no effect on HCV genotype 2a or dengue virus replicon levels. Resistance evolved more slowly to HPI than telaprevir, and HPI inhibited telaprevirresistant replicons. Molecular modeling and analysis of the ability of HPI to inhibit peptide hydrolysis catalyzed by a variety of wildtype and mutant NS3 proteins suggested that HPI forms a bridge between the NS3 RNA-binding cleft and an allosteric site previously shown to bind other protease inhibitors. In most combinations, the antiviral effect of HPI was additive with telaprevir, boceprevir, minor synergy was observed with danoprevir and modest synergy was observed with grazoprevir.

ACS chemical biology, Jan 21, 2014

Asunaprevir (ASV), an isoquinoline-based competitive inhibitor targeting the hepatitis C virus (H... more Asunaprevir (ASV), an isoquinoline-based competitive inhibitor targeting the hepatitis C virus (HCV) NS3/4A protease, is very potent in vivo. However, the potency is significantly compromised by the drug resistance mutations R155K and D168A. In this study three crystal structures of ASV and an analogue were determined to analyze the structural basis of drug resistance susceptibility. These structures revealed that ASV makes extensive contacts with Arg155 outside the substrate envelope. Arg155 in turn is stabilized by Asp168, and thus when either residue is mutated, the enzyme's interaction with…

Journal of Biological …, 2010

Transcription of HIV-1 genes depends on the RNA polymerase II kinase and elongation factor positi... more Transcription of HIV-1 genes depends on the RNA polymerase II kinase and elongation factor positive transcription elongation factor b (P-TEFb), the complex of cyclin T1 and CDK9. Recent evidence suggests that regulation of transcription by P-TEFb involves chromatin binding and modifying factors. To determine how P-TEFb may connect chromatin remodeling to transcription, we investigated the relationship between P-TEFb and histone H1. We identify histone H1 as a substrate for P-TEFb involved in cellular and HIV-1 transcription. We show that P-TEFb interacts with H1 and that P-TEFb inhibition by RNAi, flavopiridol, or dominant negative CDK9 expression correlates with loss of phosphorylation and mobility of H1 in vivo. Importantly, P-TEFb directs H1 phosphorylation in response to wild-type HIV-1 infection, but not Tat-mutant HIV-1 infection. Our results show that P-TEFb phosphorylates histone H1 at a specific C-terminal phosphorylation site. Expression of a mutant H1.1 that cannot be phosphorylated by P-TEFb also disrupts Tat transactivation in an HIV reporter cell line as well as transcription of the c-fos and hsp70 genes in HeLa cells. We identify histone H1 as a novel P-TEFb substrate, and our results suggest new roles for P-TEFb in both cellular and HIV-1 transcription.

Antiretroviral therapy to treat AIDS uses molecules that target the reverse transcriptase and pro... more Antiretroviral therapy to treat AIDS uses molecules that target the reverse transcriptase and protease enzymes of human immunodeficiency virus, type 1 (HIV-1). A major problem associated with these treatments, however, is the emergence of drug-resistant strains. Thus, there is a compelling need to find drugs against other viral targets. One such target is the interaction between Tat, an HIV-1 regulatory protein essential for viral replication, and trans-activation-responsive (TAR) RNA. Here we describe the design and synthesis of an encoded combinatorial library containing 39,304 unnatural small molecules. Using a rapid high through-put screening technology, we identified 59 compounds. Structure-activity relationship studies led to the synthesis of 19 compounds that bind TAR RNA with high affinities. In the presence of a representative Tat-TAR inhibitor (5 microM TR87), we observed potent and sustained suppression of HIV replication in cultured cells over 24 days. The same concentration of this inhibitor did not exhibit any toxicity in cell cultures or in mice. TR87 was also shown to specifically disrupt Tat-TAR binding in vitro and inhibit Tat-mediated transcriptional activation in vitro and in vivo, providing a strong correlation between its activities and inhibition of HIV-1 replication. These results provide a structural scaffold for further development of new drugs, alone or in combination with other drugs, for treatment of HIV-1-infected individuals. Our results also suggest a general strategy for discovering pharmacophores targeting RNA structures that are essential in progression of other infectious, inflammatory, and genetic diseases.

J. Am. Chem. …, 2008

The acquisition of drug-resistance mutations by infectious pathogens remains a pressing health co... more The acquisition of drug-resistance mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wildtype protease for the best binders, from K i of 30-50 nM in round one to below 100 pM in round

… Biology & Drug …, 2007

1Center for Advanced Research in Biotechnology, University of Maryland, Biotechnology Institute, ... more 1Center for Advanced Research in Biotechnology, University of Maryland, Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA 2Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical ...

PLoS Pathogens, Jul 26, 2012

Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chr... more Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term ...

Journal of virology, May 15, 2010

Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significa... more Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To ...

ACS Chemical Biology, 2013

Acquired resistance to therapeutic agents is a significant barrier to the development of clinical... more Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors for rapidly mutating enzyme targets, which we demonstrated for HIV-1 protease inhibition [Altman et al. J. Am. Chem. Soc. 2008, 130, 6099−6113]. Specifically, we developed a computational inverse design procedure with the added constraint that designed inhibitors bind entirely inside the substrate envelope, a consensus volume occupied by natural substrates. The rationale for the substrate-envelope constraint is that it prevents designed inhibitors from making interactions beyond those required by substrates and thus limits the availability of mutations tolerated by substrates but not by designed inhibitors. The strategy resulted in subnanomolar inhibitors that bind robustly across a clinically derived panel of drug-resistant variants. To further test the substrate-envelope hypothesis, here we have designed, synthesized, and assayed derivatives of our original compounds that are larger and extend outside the substrate envelope. Our designs resulted in pairs of compounds that are very similar to one another, but one respects and one violates the substrate envelope. The envelope-respecting inhibitor demonstrates robust binding across a panel of drug-resistant protease variants, whereas the envelope-violating one binds tightly to wild type but loses affinity to at least one variant. This study provides strong support for the substrate-envelope hypothesis as a design strategy for inhibitors that reduce susceptibility to resistance mutations.