Associate Professor Sim Tiow Suan

Research Interest

Anti-malarial target and drug discovery

Malaria, an age-old disease, inflicts millions of people worldwide annually, including tropical Asia (WHO, 2012). With this widespread disease and the increasing occurrence of drug-resistant Plasmodium falciparum strains, identification of unique targets for drug development is an urgent necessity. The laboratory focuses on the molecular characterisation of three classes of potential anti-malarial drug targets namely, the molecular chaperone Hsp90, cysteine proteases and kinases in the atypical MAP kinases pathway in the malaria parasite. We are interested in the molecular basis of the inhibition of these anti-malarial targets for setting up screens against a collection of natural and biotransformed products. Using a combination of in silico approaches and validation by site-directed mutagenesis, strategic amino acid residues in the targets are further identified to facilitate the design of anti-malarial compounds that are specific and selective towards the inhibition of P. falciparum.

Gene structure and function analysis: directed modification for improving antibiotic production

The possibility of improving enzymes for the biosynthesis and biotransformation of antibiotics remains a useful challenge for drug development. Isopenicillin N synthase (IPNS) and deacetoxycephalosporin C synthase (DAOCS) have been studied and have provided promising avenues to upgrade industrially important enzymes. The laboratory is interested in the genetic engineering of DAOCS to enhance the production of cephalosporins from penicillins for industrial application. Rational mutagenesis approach is employed to introduce substitutions at strategic amino acid residues in DAOCS to improve its catalytic activity and substrate specificity. The latter would allow DAOCS to accommodate a wider range of substrates to produce an expanded variety of cephalosporins.

Environmental microbiology: monitoring and endorsing microbial water quality

To support microbiological assessment of wastewater and potable water treatment systems, we have set-up a battery of tests, including standard bacteriological tests, coliphage evaluation, parasite detection, toxicity tests and PCR amplification of signature sequences for species identification.

Representative Publications

1. Chua CS, Low H, Sim TS (2014) Co-chaperones of Hsp90 in Plasmodium falciparum and their concerted roles in cellular regulation. Parasitology, 141(9): 1177-93.
2. Low H, Chua CS, Sim TS (2012) Plasmodium falciparum possesses a unique dual-specificity serine/threonine and tyrosine kinase, Pfnek3. Cellular and Molecular Life Sciences, 69(9): 1523-35.
3. Chua CS, Low H, Lehming N, Sim TS (2012) Molecular analysis of Plasmodium falciparum co-chaperone Aha1 supports its interaction with and regulation of Hsp90 in the malaria parasite. International Journal of Biochemistry and Cell Biology, 44(1): 233-245
4. Millson SH, Chua CS, Roe SM, Polier S, Solovieva S, Pearl LH, Sim TS, Prodromou C, Piper PW (2011) Features of the Streptomyces hygroscopicus HtpG reveal how partial geldanamycin resistance can arise by mutation to the ATP binding pocket of a eukaryotic Hsp90. FASEB Journal, 25(11): 3828-37.
5. Steven JW, Bachtiar M, Wang J, Sim TS, Chong SS, Lee CG (2011) An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics. The Pharmacogenomics Journal, 11(5): 315-325.
6. Chua CS, Low H, Goo KS, Sim TS (2010) Characterisation of Plasmodium falciparum co-chaperone p23: its intrinsic chaperone activity and interaction with Hsp90. Cellular and Molecular Life Sciences, 67(10): 1675-86.
7. Lin W, Chan M, Sim TS (2009) Atypical caseinolytic protease homolog from Plasmodium falciparum possesses unusual substrate preference and a functional nuclear localization signal. Parasitology Research, 105(6): 1715-22.
8. Low H, Chua CS, Sim TS (2009) Regulation of Plasmodium falciparum Pfnek3 relies on phosphorylation at its activation loop and at threonine 82. Cellular and Molecular Life Sciences, 66(18): 3081-90.
9. Goo KS, Chua CS, Sim TS (2009) Directed evolution and rational approaches to improving Streptomyces clavuligerus deacetoxycephalosporin C synthase for cephalosporin production. Journal of Industrial Microbiology & Biotechnology, 36(5): 619-633.
10. Prodromou C, Nuttall JM, Millson SH, Roe SM, Sim TS, Tan D, Workman P, Pearl LH, Piper PW. Structural Basis of the Radicicol Resistance Displayed by a Fungal Hsp90. ACS Chemical Biology, 4(4): 289-297.

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