School of Pharmacy
J. Douglas Bricker
Cancer, Docking, Homology modeling, Molecular modeling, Opportunistic infections
The results from this work are reported into two sections listed below:
Following structural classes of compounds have been designed, synthesized and studied as inhibitors of pjDHFR, RTKs and tubulin:
A total of 35 new compounds (excluding intermediates) were synthesized, characterized and submitted for biological evaluation. Results from these studies will be presented in due course. Bulk synthesis of the potent lead compound 170 was carried out to facilitate in vivo evaluation.
Docking studies were performed using LeadIT, MOE, Sybyl or Flexx for target compounds listed above and for other compounds reported by Gangjee et al. against the following targets:
1. Dihydrofolate reductase: human, P. carinii, P. jirovecii (pjDHFR) and T. gondii (tgDHFR)
2. Thymidylate synthase: human (hTS) and T. gondii (tgTS)
3. Receptor tyrosine kinases: VEGFR2, EGFR and PDGFR-β
4. Colchicine binding site of tublulin.
Novel homology models were generated and validated for pjDHFR, tgDHFR, tgTS, PDGFR-β and the F36C L65P pjDHFR double mutant. The tgTS homology model generated in this study and employed to design novel inhibitors shows remarkable similarity with the recently published X-ray crystal structures. Docking studies were performed to provide a molecular basis for the observed activity of target compounds against DHFR, RTKs or tubulin. Results from these studies support structure-based and ligand-based medicinal chemistry efforts in order to improve potency and/or selectivity of analogs of the docked compounds against these targets.
Novel topomer CoMFA models were developed for tgTS and hTS using a set of 85 bicyclic inhibitors and for RTKs using a set of 60 inhibitors reported by Gangjee et al. The resultant models could be used to explain the potency and/or selectivity differences for selected molecules for tgTS over hTS. Topomer CoMFA maps show differences in steric and/or electronic requirements among the three RTKs, and could be used, in conjuction with other medicinal chemistry approaches, to modulate the selectivity and/or potency of inhibitors with multiple RTK inhibitory potential. Drug design efforts that involve virtual library screening using these topomer CoMFA models in conjunction with traditional medicinal chemistry techniques and docking are currently underway.
Raghavan, S. (2013). Synthesis and Molecular Modeling Studies of Bicyclic Inhibitors of Dihydrofolate Reductase, Receptor Tyrosine Kinases and Tubulin (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1080