Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Ngai Ling Ma is active.

Publication


Featured researches published by Ngai Ling Ma.


Antimicrobial Agents and Chemotherapy | 2009

A small-molecule dengue virus entry inhibitor.

Qing-Yin Wang; Sejal J. Patel; Eric Vangrevelinghe; Hao Ying Xu; Ranga Rao; Deana Jaber; Wouter Schul; Feng Gu; Olivier Heudi; Ngai Ling Ma; Mee Kian Poh; Wai Yee Phong; Thomas H. Keller; Edgar Jacoby; Subhash G. Vasudevan

ABSTRACT The incidence of dengue fever epidemics has increased dramatically over the last few decades. However, no vaccine or antiviral therapies are available. Therefore, the need for safe and effective antiviral drugs has become imperative. The entry of dengue virus into a host cell is mediated by its major envelope (E) protein. The crystal structure of the E protein reveals a hydrophobic pocket that is presumably important for low-pH-mediated membrane fusion. High-throughput docking with this hydrophobic pocket was performed, and hits were evaluated in cell-based assays. Compound 6 was identified as one of the inhibitors and had an average 50% effective concentration of 119 nM against dengue virus serotype 2 in a human cell line. Mechanism-of-action studies demonstrated that compound 6 acts at an early stage during dengue virus infection. It arrests dengue virus in vesicles that colocalize with endocytosed dextran and inhibits NS3 expression. The inhibitors described in this report can serve as molecular probes for the study of the entry of flavivirus into host cells.


ACS Chemical Biology | 2012

A High-Throughput Screen To Identify Inhibitors of ATP Homeostasis in Non-replicating Mycobacterium tuberculosis

Puiying A. Mak; Srinivasa P. S. Rao; Mai Ping Tan; Xiuhua Lin; Jason Chyba; Joann Tay; Seow Hwee Ng; Bee Huat Tan; Joseph Cherian; Jeyaraj Duraiswamy; Pablo Bifani; Vivian Lim; Boon Heng Lee; Ngai Ling Ma; David Beer; Pamela Thayalan; Kelli Kuhen; Arnab K. Chatterjee; Frantisek Supek; Richard Glynne; Jun Zheng; Helena I. Boshoff; rd Clifton E. Barry; Thomas Dick; Kevin Pethe; Luis R. Camacho

Growing evidence suggests that the presence of a subpopulation of hypoxic non-replicating, phenotypically drug-tolerant mycobacteria is responsible for the prolonged duration of tuberculosis treatment. The discovery of new antitubercular agents active against this subpopulation may help in developing new strategies to shorten the time of tuberculosis therapy. Recently, the maintenance of a low level of bacterial respiration was shown to be a point of metabolic vulnerability in Mycobacterium tuberculosis. Here, we describe the development of a hypoxic model to identify compounds targeting mycobacterial respiratory functions and ATP homeostasis in whole mycobacteria. The model was adapted to 1,536-well plate format and successfully used to screen over 600,000 compounds. Approximately 800 compounds were confirmed to reduce intracellular ATP levels in a dose-dependent manner in Mycobacterium bovis BCG. One hundred and forty non-cytotoxic compounds with activity against hypoxic non-replicating M. tuberculosis were further validated. The resulting collection of compounds that disrupt ATP homeostasis in M. tuberculosis represents a valuable resource to decipher the biology of persistent mycobacteria.


Journal of Antimicrobial Chemotherapy | 2008

Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis

Mekonnen Kurabachew; Stephen H. J. Lu; Philipp Krastel; Esther K. Schmitt; Bangalore L. Suresh; Anne Goh; John E. Knox; Ngai Ling Ma; Jan Jiricek; David Beer; Michael H. Cynamon; Frank Petersen; Véronique Dartois; Thomas H. Keller; Thomas Dick; Vasan K. Sambandamurthy

OBJECTIVES The aim of this study was to determine the in vitro activity of lipiarmycin against drug-resistant strains of Mycobacterium tuberculosis (MTB) and to establish the resistance mechanism of MTB against lipiarmycin using genetic approaches. METHODS MIC values were measured against a panel of drug-resistant strains of MTB using the broth microdilution method. Spontaneous lipiarmycin-resistant mutants of MTB were tested for cross-resistance to standard anti-TB drugs, and their rpoB and rpoC genes were sequenced to identify mutations. RESULTS Lipiarmycin exhibited excellent inhibitory activity against multidrug-resistant strains of MTB with MIC values of <0.1 mg/L. Sequence analysis of the rpoB and rpoC genes from spontaneous lipiarmycin-resistant mutants of MTB revealed that missense mutations in these genes caused resistance to lipiarmycin. Although both lipiarmycin and rifampicin are known to inhibit the bacterial RNA polymerase, the sites of mutation in the rpoB gene were found to be different in MTB strains resistant to these inhibitors. Whereas all six rifampicin-resistant MTB strains tested had mutation in the 81 bp hotspot region of the rpoB gene spanning codons 507-533, 16 of 18 lipiarmycin-resistant strains exhibited mutation between codons 977 and 1150. The remaining two lipiarmycin-resistant strains had mutation in the rpoC gene. CONCLUSIONS Lipiarmycin has excellent bactericidal activity against MTB and lacks cross-resistance to standard anti-TB drugs. Furthermore, rifampicin-resistant strains remained fully susceptible to lipiarmycin, and none of the lipiarmycin-resistant MTB strains became resistant to rifampicin, highlighting the lack of cross-resistance.


Journal of Medicinal Chemistry | 2013

Design, synthesis, and biological evaluation of indole-2-carboxamides: a promising class of antituberculosis agents.

Ravinder Reddy Kondreddi; Jan Jiricek; Srinivasa Rao; Suresh B. Lakshminarayana; Luis R. Camacho; Ranga Rao; Maxime Herve; Pablo Bifani; Ngai Ling Ma; Kelli Kuhen; Anne Goh; Arnab K. Chatterjee; Thomas Dick; Thierry T. Diagana; Ujjini H. Manjunatha; Paul W. Smith

Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One of the hits, indole-2-carboxamide analog (1), had low micromolar potency against Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and low aqueous solubility. Structure-activity relationship studies revealed that attaching alkyl groups to the cyclohexyl ring significantly improved Mtb activity but reduced solubility. Furthermore, chloro, fluoro, or cyano substitutions on the 4- and 6-positions of the indole ring as well as methyl substitution on the cyclohexyl ring significantly improved metabolic stability. 39 and 41, the lead candidates, displayed improved in vitro activity compared to most of the current standard TB drugs. The low aqueous solubility could not be mitigated because of the positive correlation of lipophilicity with Mtb potency. However, both compounds displayed favorable oral pharmacokinetic properties in rodents and demonstrated in vivo efficacy. Thus, indole-2-carboxamides represent a promising new class of antituberculosis agents.


European Journal of Medicinal Chemistry | 2015

Structure activity relationships of 4-hydroxy-2-pyridones: A novel class of antituberculosis agents

Pearly Shuyi Ng; Ujjini H. Manjunatha; Srinivasa P. S. Rao; Luis R. Camacho; Ngai Ling Ma; Maxime Herve; Christian G. Noble; Anne Goh; Stefan Peukert; Thierry T. Diagana; Paul W. Smith; Ravinder Reddy Kondreddi

Pyridone 1 was identified from a high-throughput cell-based phenotypic screen against Mycobacterium tuberculosis (Mtb) including multi-drug resistant tuberculosis (MDR-TB) as a novel anti-TB agent and subsequently optimized series using cell-based Mtb assay. Preliminary structure activity relationship on the isobutyl group with higher cycloalkyl groups at 6-position of pyridone ring has enabled us to significant improvement of potency against Mtb. The lead compound 30j, a dimethylcyclohexyl group on the 6-position of the pyridone, displayed desirable in vitro potency against both drug sensitive and multi-drug resistant TB clinical isolates. In addition, 30j displayed favorable oral pharmacokinetic properties and demonstrated in vivo efficacy in mouse model. These results emphasize the importance of 4-hydroxy-2-pyridones as a new chemotype and further optimization of properties to treat MDR-TB.


Antimicrobial Agents and Chemotherapy | 2010

Preclinical Evaluation of the Antifolate QN254, 5-Chloro- N′6′-(2,5-Dimethoxy-Benzyl)-Quinazoline-2,4,6-Triamine, as an Antimalarial Drug Candidate

Alexis Nzila; Matthias Rottmann; Penchit Chitnumsub; Stevens M. Kiara; Sumalee Kamchonwongpaisan; Cherdsak Maneeruttanarungroj; Bryan K. S. Yeung; Anne Goh; Suresh B. Lakshminarayana; Bin Zou; Josephine Wong; Ngai Ling Ma; Margaret Weaver; Thomas H. Keller; Véronique Dartois; Sergio Wittlin; Reto Brun; Yongyuth Yuthavong; Thierry T. Diagana

ABSTRACT Drug resistance against dihydrofolate reductase (DHFR) inhibitors—such as pyrimethamine (PM)—has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N′6′-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.


Journal of Computer-aided Molecular Design | 2013

The importance of molecular complexity in the design of screening libraries.

Shahul Nilar; Ngai Ling Ma; Thomas H. Keller

The one-dimensional model of Hann et al. (J Chem Inf Comput Sci 41(3):856–864) has been extended to include reverse binding and wrap-around interaction modes between the protein and ligand to explore the complete combinatorial matrix of molecular recognition. The cumulative distribution function of the Maxwell–Boltzmann distribution has been used to calculate the probability of measuring the sensitivity of the interactions as the asymptotic limits of the distribution better describe the behavior of the interactions under experimental conditions. Based on our model, we hypothesized that molecules of lower complexity are preferred for target based screening campaigns, while augmenting such a library with moieties of moderate complexities maybe better suited for phenotypic screens. The validity of the hypothesis has been assessed via the analysis of the hit rate profiles for four ChemBL datasets for enzymatic and phenotypic screens.


Current Computer - Aided Drug Design | 2016

Artificial Neural Network Analysis of Pharmacokinetic and Toxicity Properties of Lead Molecules for Dengue Fever, Tuberculosis and Malaria

Shahul Nilar; Suresh B. Lakshminarayana; Ngai Ling Ma; Thomas H. Keller; Francesca Blasco; Paul W. Smith

Poor pharmacokinetic and toxicity profiles are major reasons for the low rate of advancing lead drug candidates into efficacy studies. The In-silico prediction of primary pharmacokinetic and toxicity properties in the drug discovery and development process can be used as guidance in the design of candidates. In-silico parameters can also be used to choose suitable compounds for in-vivo testing thereby reducing the number of animals used in experiments. At the Novartis Institute for Tropical Diseases, a data set has been curated from in-house measurements in the disease areas of Dengue, Tuberculosis and Malaria. Volume of distribution, half-life, total in-vivo clearance, in-vitro human plasma protein binding and in-vivo oral bioavailability have been measured for molecules in the lead optimization stage in each of these three disease areas. Data for the inhibition of the hERG channel using the radio ligand binding dofetilide assay was determined for a set of 300 molecules in these therapeutic areas. Based on this data, Artificial Neural Networks were used to construct In-silico models for each of the properties listed above that can be used to prioritize candidates for lead optimization and to assist in selecting promising molecules for in-vivo pharmacokinetic studies.


Bioorganic & Medicinal Chemistry Letters | 2006

Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors.

Zheng Yin; Sejal J. Patel; Wei-Ling Wang; Wai-Ling Chan; K.R. Ranga Rao; Gang Wang; Xinyi Ngew; Viral Patel; David Beer; John E. Knox; Ngai Ling Ma; Claus Ehrhardt; Siew Pheng Lim; Subhash G. Vasudevan; Thomas H. Keller


Antiviral Research | 2009

A small molecule fusion inhibitor of dengue virus

Mee Kian Poh; Andy Yip; Summer Zhang; John P. Priestle; Ngai Ling Ma; Jolanda M. Smit; Jan Wilschut; Pei Yong Shi; Markus R. Wenk; Wouter Schul

Collaboration


Dive into the Ngai Ling Ma's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Thomas Dick

National University of Singapore

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Arnab K. Chatterjee

Genomics Institute of the Novartis Research Foundation

View shared research outputs
Researchain Logo
Decentralizing Knowledge