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Wayne Guida, PhD

Research Program: Molecular Medicine Program

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  • Overview

    The Guida Lab uses computational modeling to discover and design novel therapeutic agents for the treatment of cancer.


    • Molecular Oncology & Drug Discovery Program
    • Molecular Medicine Program

    Education & Training


    • University of South Florida, PhD - Organic Chemistry


    • Duke University - Bio-organic Chemistry
    • Columbia University - Computational Chemistry
  • Research Interest

    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 and 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.

  • Publications

    • Sparks RP, Arango AS, Starr ML, Aboff ZL, Hurst LR, Rivera-Kohr DA, Zhang C, Harnden KA, Jenkins JL, Guida WC, Tajkhorshid E, Fratti RA. Correction: A small-molecule competitive inhibitor of phosphatidic acid binding by the AAA+ protein NSF/Sec18 blocks the SNARE-priming stage of vacuole fusion. J Biol Chem. 2022 Nov.298(11):102576. Pubmedid: 36257250. Pmcid: PMC9579040.
    • Tur J, Badole SL, Manickam R, Chapalamadugu KC, Xuan W, Guida W, Crews JJ, Bisht KS, Tipparaju SM. Cardioprotective Effects of 1-(3,6-Dibromo-carbazol-9-yl)-3-Phenylamino-Propan-2-Ol in Diabetic Hearts via Nicotinamide Phosphoribosyltransferase Activation. J Pharmacol Exp Ther. 2022 Aug.382(2):233-245. Pubmedid: 35680376. Pmcid: PMC9372916.
    • Burgos M, Philippe R, Antigny F, Buscaglia P, Masson E, Mukherjee S, Dubar P, Le Maréchal C, Campeotto F, Lebonvallet N, Frieden M, Llopis J, Domingo B, Stathopulos PB, Ikura M, Brooks W, Guida W, Chen JM, Ferec C, Capiod T, Mignen O. The p.E152K-STIM1 mutation deregulates Ca2+ signaling contributing to chronic pancreatitis. J Cell Sci. 2021 Feb.134(3). Pubmedid: 33468626.
    • Sparks RP, Arango AS, Jenkins JL, Guida WC, Tajkhorshid E, Sparks CE, Sparks JD, Fratti RA. An Allosteric Binding Site on Sortilin Regulates the Trafficking of VLDL, PCSK9, and LDLR in Hepatocytes. Biochemistry-Us. 2020 Nov.59(45):4321-4335. Pubmedid: 33153264. Pmcid: PMC7674269.
    • Sparks RP, Lui A, Bader D, Patel R, Murr M, Guida W, Fratti RA, Patel NA. A specific small-molecule inhibitor of protein kinase CδI activity improves metabolic dysfunction in human adipocytes from obese individuals. J Biol Chem. 2019 Oct.294(41):14896-14910. Pubmedid: 31413114. Pmcid: PMC6791326.
    • Sparks RP, Arango AS, Starr ML, Aboff ZL, Hurst LR, Rivera-Kohr DA, Zhang C, Harden KA, Jenkins JL, Guida WC, Tajkhorshid E, Fratti RA. A small-molecule competitive inhibitor of phosphatidic acid binding by the AAA+ protein NSF/Sec18 blocks the SNARE-priming stage of vacuole fusion. J Biol Chem. 2019 Nov.294(46):17168-17185. Pubmedid: 31515268. Pmcid: PMC6873166.
    • Handa S, Dempsey DR, Ramamoorthy D, Cook N, Guida WC, Spradling TJ, White JK, Woodcock HL, Merkler DJ. Mechanistic Studies of 1-Deoxy-D-Xylulose-5-Phosphate Synthase from Deinococcus radiodurans. Biochem Mol Biol J. 2018 Mar.4(1). Pubmedid: 29552677. Pmcid: PMC5851014.
    • Akuffo AA, Alontaga AY, Metcalf R, Beatty MS, Becker A, McDaniel JM, Hesterberg RS, Goodheart WE, Gunawan S, Ayaz M, Yang Y, Karim MR, Orobello ME, Daniel K, Guida W, Yoder JA, Rajadhyaksha AM, Schonbrunn E, Lawrence HR, Lawrence NJ, Epling-Burnette PK. Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon. J Biol Chem. 2018 Apr.293(16):6187-6200. Pubmedid: 29449372. Pmcid: PMC5912449.
    • Mukherjee S, Karolak A, Debant M, Buscaglia P, Renaudineau Y, Mignen O, Guida WC, Brooks WH. Molecular Dynamics Simulations of Membrane-Bound STIM1 to Investigate Conformational Changes during STIM1 Activation upon Calcium Release. J Chem Inf Model. 2017 02.57(2):335-344. Pubmedid: 28151650.
    • Sparks RP, Jenkins JL, Miner GE, Wang Y, Guida WC, Sparks CE, Fratti RA, Sparks JD. Phosphatidylinositol (3,4,5)-trisphosphate binds to sortilin and competes with neurotensin: Implications for very low density lipoprotein binding. Biochem Bioph Res Co. 2016 Oct.479(3):551-556. Pubmedid: 27666481. Pmcid: PMC5056161.
    • Sparks RP, Guida WC, Sowden MP, Jenkins JL, Starr ML, Fratti RA, Sparks CE, Sparks JD. Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells. Biochem Bioph Res Co. 2016 09.478(2):546-552. Pubmedid: 27495870. Pmcid: PMC5002383.
    • Mukherjee S, Sparks R, Metcalf R, Brooks W, Daniel K, Guida WC. Cupriphilic compounds to aid in proteasome inhibition. Bioorg Med Chem Lett. 2016 08.26(15):3826-3829. Pubmedid: 27311892.
    • Kang CW, Sarnowski MP, Ranatunga S, Wojtas L, Metcalf RS, Guida WC, Del Valle JR. β-Strand mimics based on tetrahydropyridazinedione (tpd) peptide stitching. Chem Commun (Camb). 2015 Nov.51(90):16259-16262. Pubmedid: 26400240. Pmcid: PMC5561724.
    • Doupnik CA, Parra KC, Guida WC. A computational design approach for virtual screening of peptide interactions across K(+) channel families. Comput Struct Biotechnol J. 2015.13:85-94. Pubmedid: 25709757. Pmcid: PMC4334993.
    • Cross RM, Flanigan DL, Monastyrskyi A, LaCrue AN, Sáenz FE, Maignan JR, Mutka TS, White KL, Shackleford DM, Bathurst I, Fronczek FR, Wojtas L, Guida WC, Charman SA, Burrows JN, Kyle DE, Manetsch R. Orally bioavailable 6-chloro-7-methoxy-4(1H)-quinolones efficacious against multiple stages of Plasmodium. J Med Chem. 2014 Nov.57(21):8860-8879. Pubmedid: 25148516. Pmcid: PMC4234439.
    • Campbell CO, Santiago DN, Guida WC, Manetsch R, Adams JH. In silico characterization of an atypical MAPK phosphatase of Plasmodium falciparum as a suitable target for drug discovery. Chem Biol Drug Des. 2014 Aug.84(2):158-168. Pubmedid: 24605883. Pmcid: PMC4497549.
    • Ozcan S, Kazi A, Marsilio F, Fang B, Guida WC, Koomen J, Lawrence HR, Sebti SM. Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors. J Med Chem. 2013 May.56(10):3783-3805. Pubmedid: 23547706. Pmcid: PMC3774303.
    • 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 May.53(5):1138-1156. 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. Pmcid: PMC4030628.
    • Handa S, Ramamoorthy D, Spradling TJ, Guida WC, Adams JH, Bendinskas KG, Merkler DJ. Production of recombinant 1-deoxy-d-xylulose-5-phosphate synthase from Plasmodium vivax in Escherichia coli. FEBS Open Bio. 2013 Jun.3:124-129. Pubmedid: 23772383. Pmcid: PMC3668541.
    • Urlam MK, Pireddu R, Ge Y, Zhang X, Sun Y, Lawrence HR, Guida WC, Sebti SM, Lawrence NJ. Development of new N-Arylbenzamides as STAT3 Dimerization Inhibitors. Medchemcomm. 2013 Jun.4(6):932-941. Pubmedid: 24073326. Pmcid: PMC3780559.
    • 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.
    • 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. Pmcid: PMC4516226.
    • 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. Pmcid: PMC3531244.
    • 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.
    • 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. Pmcid: PMC5765859.
    • 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.
    • 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, 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.
    • 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.
    • 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.
    • 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-Us. 2009 Jul.48(27):6423-6430. Pubmedid: 19527050. Pmcid: PMC2730737.
    • 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.
    • Brooks W, Daniel K, Sung S, Guida W. Computational validation of the importance of absolute stereochemistry in virtual screening. J Chem Inf Model. 2008 Mar.48(3):639-645. Pubmedid: 18266348.
    • 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, 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 Nov.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. Pmcid: PMC1863497.
    • 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.
    • 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.
    • 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):871-885. Pubmedid: 16607571.
    • Daniel K, Harbach R, Guida W, Dou Q. Copper storage diseases: Menkes, Wilsons, and cancer. Front Biosci (Landmark Ed). 2004 Sep.9:2652-2662. Pubmedid: 15358588.
    • 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 Mar.67(6):1139-1151. Pubmedid: 15006550.
    • 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.
    • Cheltsov A, Guida W, Ferreira G. Circular permutation of 5-aminolevulinate synthase: effect on folding, conformational stability, and structure. J Biol Chem. 2003 Jul.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 Jan.13(1):107-110. Pubmedid: 12467627.
    • 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 Nov.124(45):13448-13453. Pubmedid: 12418897.
    • 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.
    • Guida WC, Elliott RD, Thomas HJ, Secrist JA, Babu YS, Bugg CE, Erion MD, Ealick SE, Montgomery JA. Structure-based design of inhibitors of purine nucleoside phosphorylase. 4. A study of phosphate mimics. J Med Chem. 1994 Apr.37(8):1109-1114. Pubmedid: 8164252.
    • Erion MD, Niwas S, Rose JD, Ananthan S, Allen M, Secrist JA, Babu YS, Bugg CE, Guida WC, Ealick SE. Structure-based design of inhibitors of purine nucleoside phosphorylase. 3. 9-Arylmethyl derivatives of 9-deazaguanine substituted on the methylene group. J Med Chem. 1993 Nov.36(24):3771-3783. Pubmedid: 8254607.
    • Secrist JA, Niwas S, Rose JD, Babu YS, Bugg CE, Erion MD, Guida WC, Ealick SE, Montgomery JA. Structure-based design of inhibitors of purine nucleoside phosphorylase. 2. 9-Alicyclic and 9-heteroalicyclic derivatives of 9-deazaguanine. J Med Chem. 1993 Jun.36(13):1847-1854. Pubmedid: 8515423.
    • Montgomery JA, Niwas S, Rose JD, Secrist JA, Babu YS, Bugg CE, Erion MD, Guida WC, Ealick SE. Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(arylmethyl) derivatives of 9-deazaguanine. J Med Chem. 1993 Jan.36(1):55-69. Pubmedid: 8421291.
    • Ealick SE, Babu YS, Bugg CE, Erion MD, Guida WC, Montgomery JA, Secrist JA. Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors. Proc Natl Acad Sci U S A. 1991 Dec.88(24):11540-11544. Pubmedid: 1763067. Pmcid: PMC53171.
    • Bohacek RS, Guida WC. A rapid method for the computation, comparison and display of molecular volumes. J Mol Graph. 1989 Jun.7(2):113-117. Pubmedid: 2488264.

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