Wayne Charles Guida, PhD

My research is focused on computer aided drug design. An area of specific interest to our lab is the design of enzymes essential for the biosynthesis of polyamines, which are critical for the replication of DNA and are elevated in a number of human tumors. This work has focused on the design of S-adenosylmethionin decarboxylase inhibitors as potential anti-cancer agents.

Through collaboration with other investigators at Moffitt, we have been involved in the computational design of inhibitors of other enzymes adn inhibitors of protein-protein interactions that have therapeutic releveance in cancer.  This work includes the following biomolecular targets: farnesyl transferase and geranylgeranyl transferase (in collaboration with Drs. Said Sebti and Nick Lawrence), the 20S Proteasome (with Drs. Said Sebti and Mark McLaughlin), MDM2 p53 and MDMX-P53 (with Drs. Jiandong Chen and Mark McLaughlin) and Shp2 (with Drs. Jerry Wu and Nick Lawrence).

We are also interested in developing enhanced methods for the docking of inhibitors into protein binding sites and in applying computational techniques to the problem of elucidating the mechanistic details of enzyme catalysis and in the design, synthesis, and study of model complexes that mimic zinc metallproteases.

• Ozcan S, Kazi A, Marsilio F, Fang B, Guida WC, Koomen JM, Lawrence H, Sebti SM. Oxadiazole-isopropylamides as Potent and Noncovalent Proteasome Inhibitors. J Med Chem. 2013 May. Pubmedid: 23547706.
• Ramamoorthy D, Turos E, Guida WC. Identification of a New Binding Site in E. coli FabH using Molecular Dynamics Simulations: Validation by Computational Alanine Mutagenesis and Docking Studies. J Chem Inf Model. 2013 Apr. Pubmedid: 23581389.
• Zhang X, Sun Y, Pireddu R, Yang H, Urlam MK, Lawrence HR, Guida WC, Lawrence NJ, Sebti SM. A Novel Inhibitor of STAT3 Homodimerization Selectively Suppresses STAT3 Activity and Malignant Transformation. Cancer Res. 2013 Mar;73(6):1922-1933. Pubmedid: 23322008.
• Kim YB, Balasis ME, Doi K, Berndt N, DuBoulay C, Hu CC, Guida W, Wang HG, Sebti SM, Del Valle JR. Synthesis and evaluation of substituted hexahydronaphthalenes as novel inhibitors of the Mcl-1/BimBH3 interaction. Bioorg Med Chem Lett. 2012 Sep;22(18):5961-5965. Pubmedid: 22901384. Pmcid: PMC3432503.
• Santiago DN, Pevzner Y, Durand AA, Tran M, Scheerer RR, Daniel K, Sung SS, Woodcock HL, Guida WC, Brooks WH. Virtual target screening: validation using kinase inhibitors. J Chem Inf Model. 2012 Aug;52(8):2192-2203. Pubmedid: 22747098. Pmcid: PMC3488111.
• Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM, Lawrence NJ. Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2). Medchemcomm. 2012 Jun;3(6):699-709. Pubmedid: 23275831.
• Ge Y, Kazi A, Marsilio F, Luo Y, Jain S, Brooks W, Daniel KG, Guida WC, Sebti SM, Lawrence HR. Discovery and synthesis of hydronaphthoquinones as novel proteasome inhibitors. J Med Chem. 2012 Mar;55(5):1978-1998. Pubmedid: 22220566. Pmcid: PMC3530929.
• Li R, Martin MP, Liu Y, Wang B, Patel RA, Zhu JY, Sun N, Pireddu R, Lawrence NJ, Li J, Haura EB, Sung SS, Guida WC, Schonbrunn E, Sebti SM. Fragment-based and structure-guided discovery and optimization of rho kinase inhibitors. J Med Chem. 2012 Mar;55(5):2474-2478. Pubmedid: 22272748.
• Scott LM, Chen L, Daniel KG, Brooks WH, Guida WC, Lawrence HR, Sebti SM, Lawrence NJ, Wu J. Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs. Bioorg Med Chem Lett. 2011 Jan;21(2):730-733. Pubmedid: 21193311. Pmcid: PMC3034307.
• Brooks WH, Guida WC, Daniel KG. The significance of chirality in drug design and development. Curr Top Med Chem. 2011;11(7):760-770. Pubmedid: 21291399.
• Chen L, Pernazza D, Scott LM, Lawrence HR, Ren Y, Luo Y, Wu X, Sung SS, Guida WC, Sebti SM, Lawrence NJ, Wu J. Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112. Biochem Pharmacol. 2010 Sep;80(6):801-810. Pubmedid: 20510203. Pmcid: PMC2906681.
• Lawrence HR, Kazi A, Luo Y, Kendig R, Ge Y, Jain S, Daniel K, Santiago D, Guida WC, Sebti SM. Synthesis and biological evaluation of naphthoquinone analogs as a novel class of proteasome inhibitors. Bioorg Med Chem. 2010 Aug;18(15):5576-5592. Pubmedid: 20621484. Pmcid: PMC3530924.
• Anderson L, Zhou M, Sharma V, McLaughlin JM, Santiago DN, Fronczek FR, Guida WC, McLaughlin ML. Facile iterative synthesis of 2,5-terpyrimidinylenes as nonpeptidic alpha-helical mimics. J Org Chem. 2010 Jun;75(12):4288-4291. Pubmedid: 20469918. Pmcid: PMC2901110.
• Phan J, Li Z, Kasprzak A, Li B, Sebti S, Guida W, Schönbrunn E, Chen J. Structure-based design of high affinity peptides inhibiting the interaction of p53 with MDM2 and MDMX. J Biol Chem. 2010 Jan;285(3):2174-2183. Pubmedid: 19910468. Pmcid: PMC2804373.
• Lawrence HR, Li Z, Yip ML, Sung SS, Lawrence NJ, McLaughlin ML, McManus GJ, Zaworotko MJ, Sebti SM, Chen J, Guida WC. Identification of a disruptor of the MDM2-p53 protein-protein interaction facilitated by high-throughput in silico docking. Bioorg Med Chem Lett. 2009 Jul;19(14):3756-3759. Pubmedid: 19457663. Pmcid: PMC2754843.
• Bale S, Brooks W, Hanes JW, Mahesan AM, Guida WC, Ealick SE. Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase. Biochemistry. 2009 Jul;48(27):6423-6430. Pubmedid: 19527050. Pmcid: PMC2730737.
• Kazi A, Lawrence H, Guida WC, McLaughlin ML, Springett GM, Berndt N, Yip RM, Sebti SM. Discovery of a novel proteasome inhibitor selective for cancer cells over non-transformed cells. Cell Cycle. 2009 Jun;8(12):1940-1951. Pubmedid: 19471122. Pmcid: PMC2892826.
• McCloskey DE, Bale S, Secrist JA, Tiwari A, Moss TH, Valiyaveettil J, Brooks WH, Guida WC, Pegg AE, Ealick SE. New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine. J Med Chem. 2009 Mar;52(5):1388-1407. Pubmedid: 19209891. Pmcid: PMC2652407.
• Pauly GT, Loktionova NA, Fang Q, Vankayala SL, Guida WC, Pegg AE. Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine. J Med Chem. 2008 Nov;51(22):7144-7153. Pubmedid: 18973327. Pmcid: PMC2645950.
• Ma Y, Kurtyka CA, Boyapalle S, Sung SS, Lawrence H, Guida W, Cress WD. A small-molecule E2F inhibitor blocks growth in a melanoma culture model. Cancer Res. 2008 Aug;68(15):6292-6299. Pubmedid: 18676853. Pmcid: PMC3615411.
• Lawrence HR, Pireddu R, Chen L, Luo Y, Sung SS, Szymanski AM, Yip ML, Guida WC, Sebti SM, Wu J, Lawrence NJ. Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds. J Med Chem. 2008 Aug;51(16):4948-4956. Pubmedid: 18680359. Pmcid: PMC2744494.
• Brooks W, Daniel K, Sung S, Guida W. Computational Validation of the Importance of Absolute Stereochemistry in VirtualScreening. J Chem Inf Model. 2008 Mar;48(3):639-645. Pubmedid: 18266348.
• Brooks W, McCloskey D, Daniel K, Ealick S, Secrist JA 3rd, Waud W, Pegg AE, Guida W. In Silico Chemical Library Screening and Experimental Validation of a Novel 9-Aminoacridine Based Lead-Inhibitor of Human S-Adenosylmethionine Decarboxylase. J Chem Inf Model. 2007 Aug;47(5):1897-1905. Pubmedid: 17676832.
• Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR, Yip ML, Jove R, McLaughlin MM, Lawrence NJ, Sebti SM, Turkson J. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A. 2007 May;104(18):7391-7396. Pubmedid: 17463090.
• Chen L, Sung SS, Yip ML, Lawrence HR, Ren Y, Guida WC, Sebti SM, Lawrence NJ, Wu J. Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Mol Pharmacol. 2006 Aug;70(2):562-570. Pubmedid: 16717135.
• Guida W, Hamilton A, Crotty J, Sebti S. Protein farnesyltransferase: Flexible docking studies on inhibitors using computational modeling. J Comput Aided Mol Des. 2005 Dec;19(12):871-85. Pubmedid: 16607571.
• Maheshwari A, Lu W, Guida W, Christensen R, Calhoun D. IL-8/CXC ligand 8 survives neonatal gastric digestion as a result of intrinsic aspartyl proteinase resistance. Pediatr Res. 2005 Mar;57(3):438-444. Pubmedid: 15585673.
• Smith DM, Daniel KG, Wang Z, Guida WC, Chan TH, Dou QP. Docking studies and model development of tea polyphenol proteasome inhibitors: applications to rational drug design. Proteins. 2004 Jan;54(1):58-70. Pubmedid: 14705024.
• Daniel K, Gupta P, Harbach R, Guida W, Dou Q. Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells. Biochem Pharmacol. 2004;67(6):1139-1151. Pubmedid: 15006550.
• Daniel K, Harbach R, Guida W, Dou Q. Copper storage diseases: Menkes, Wilsons, and cancer. Front Biosci. 2004;9(21):2652-2662. Pubmedid: 15358588.
• Cheltsov A, Guida W, Ferreira G. Circular permutation of 5-aminolevulinate synthase: effect on folding, conformational stability, and structure. J Biol Chem. 2003;278(30):27945-27955. Pubmedid: 12736261.
• Price M, Guida W, Jackson T, Nydick J, Gladstone P, Juarez J, Donate F, Ternansky R. Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model. Bioorg Med Chem Lett. 2003;13(1):107-110. Pubmedid: 12467627.
• Klicic J, Friesner R, Liu S, Guida W. Accurate prediction of acidity constants in aqueous solution via density functional theory and self-consistent reaction field method. J Phys Chem B. 2002;106:1327-1335. Pubmedid: noPMID.
• Gawley R, Pinet S, Cardona C, Datta P, Ren T, Guida W, Nydick J, Leblanc R. Chemosensors for the marine toxin saxitoxin. J Am Chem Soc. 2002;124(45):13448-13448. Pubmedid: 12418897.