Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Rational Design of Small-Molecule Inhibitors of Protein-Protein Interactions: Application to the Oncogenic c-Myc/Max Interaction

Meireles, Lidio Marx Carvalho (2011) Rational Design of Small-Molecule Inhibitors of Protein-Protein Interactions: Application to the Oncogenic c-Myc/Max Interaction. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (3MB) | Preview


Protein-protein interactions (PPIs) constitute an emerging class of targets for pharmaceutical intervention pursued by both industry and academia. Despite their fundamental role in many biological processes and diseases such as cancer, PPIs are still largely underrepresented in today's drug discovery. This dissertation describes novel computational approaches developed to facilitate the discovery/design of small-molecule inhibitors of PPIs, using the oncogenic c-Myc/Max interaction as a case study.First, we critically review current approaches and limitations to the discovery of small-molecule inhibitors of PPIs and we provide examples from the literature.Second, we examine the role of protein flexibility in molecular recognition and binding, and we review recent advances in the application of Elastic Network Models (ENMs) to modeling the global conformational changes of proteins observed upon ligand binding. The agreement between predicted soft modes of motions and structural changes experimentally observed upon ligand binding supports the view that ligand binding is facilitated, if not enabled, by the intrinsic (pre-existing) motions thermally accessible to the protein in the unliganded form.Third, we develop a new method for generating models of the bioactive conformations of molecules in the absence of protein structure, by identifying a set of conformations (from different molecules) that are most mutually similar in terms of both their shape and chemical features. We show how to solve the problem using an Integer Linear Programming formulation of the maximum-edge weight clique problem. In addition, we present the application of the method to known c-Myc/Max inhibitors.Fourth, we propose an innovative methodology for molecular mimicry design. We show how the structure of the c-Myc/Max complex was exploited to designing compounds that mimic the binding interactions that Max makes with the leucine zipper domain of c-Myc.In summary, the approaches described in this dissertation constitute important contributions to the fields of computational biology and computer-aided drug discovery, which combine biophysical insights and computational methods to expedite the discovery of novel inhibitors of PPIs.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Meireles, Lidio Marx Carvalholmm85@pitt.eduLMM85
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBahar, Ivetbahar@pitt.eduBAHAR
Committee CoChairMustata, Gabrielagmustata@pitt.eduGMUSTATA
Committee MemberChennubhotla, Chakrachakracs@pitt.eduCHAKRACS
Committee MemberProchownik,
Committee MemberRule,
Date: 7 September 2011
Date Type: Completion
Defense Date: 26 July 2011
Approval Date: 7 September 2011
Submission Date: 4 August 2011
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: drug design; drug discovery; oncogene; protein-protein interactions; small-molecule inhibitors
Other ID:, etd-08042011-233540
Date Deposited: 10 Nov 2011 19:57
Last Modified: 15 Nov 2016 13:48


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item