Issued as Final progress report, Project G-33-51

Suddath, Fred Leroy

Scholarly Materials And Research @ Georgia Tech

15:29:40 DCA PAD AMENDMENT - PROJECT HEADER INFORMATION Project 1: G-33-515 Cost share 1: Center I : 10/ll-6-P5066-3AO Center shr 1: Rev 1: 2 DCA file 1: 03/19/92 Active Work type : RES Contract#: 5 F32 HL07994-03 Prime 1: Subprojects ? : N Main project 1: Project unit: Project director(s): SUDDATH F L JR CHEMISTRY CHEMISTRY Sponsor/division names: DHHS/PHS/NIH Sponsor/division codes: 108 Mod 1: LTR DTD 3/6/92 Document GRANT Contract entity: GTRC CFDA: PE 1: Unit code: 02.010.136 (404)894-4028 I NATL INSTITUTES OF HEALTH I 001 Award period: 910118 to 930102 (performance) 930402 (reports) Sponsor amount Contract value Funded Cost sharing amount New this change 0.00 0.00 Does subcontracting plan apply ?: N Total to date 28,789.69 28,789.69 0.00 Title: MOLECULAR MODELING OF INHIBITOR - PROTEASE COMPLEXES PROJECT ADMINISTRATION DATA DCA contact: Kathleen R. Ehlinger Sponsor technical contact MS. MARY S. REILLY (301)496-7668 NIH/NAT. HEART,LUNG, & BLOOD INST. 9000 ROCKVILLE PIKE BETHESDA, MD. 20892 Security class (U,C,S,TS) : U Defense priority rating Equipment title vests with: NONE PROPOSED. Administrative comments -N/A Sponsor 894-4820 Sponsor issuing office PHYLLIS Y. FINCH, GRANTS MANAGEMENT (301)496-4970 NIH/NAT. HEART, LUNG, & BLOOD INST. 9000 ROCKVILLE PIKE BETHESDA, MD 20892 ISSUED TO EXTEND TERMINATION DATE FROM 1/2/92 TO 1/2/93. GEORGIA INSTITUTE OF .TECHNOLOGV OFFICE OF CONTRACT ADMINISTRATION NOTICE OF PROJECT CLOSEOUT Closeout Notice Date 09/03/92 Project No. G-33-515 _______________ __ Center No. 10/ll-6-P5066-3AO_ Project Director 3t:JBBATII F L JR ____ _ School/Lab CHEMISTRY ______ _ Sponsor DHHS/PHS/NIH/NATL INSTITUTES OF HEALTH __________________ ___ Contract/Grant No. 5 F32 Hl07994-03 ____________ ~ Contract Entity GTRC Prime Contract No. Title MOLECULAR MODELING OF INHIBITOR - PROTEASE COMPLEXES ________________ __ Effective Completion Date 930102 (Performance) 930402 <Reports) Closeout Actions Required: Final Invoice or Copy of Final Invoice Final Report of ~nventions and/or Subcontracts Government Property Inventory 8 Related Certificate Classified Material Certificate V/N N v N N Release and Assignment N Other N Date Submitted .......... _ .. --CommentsPATENT REPORT = DHHS 568, ATTACHED ______________________________ __ Subproject Under Main Project No. Continues Project No. Distribution Required: Project Director Administrative Network Representative GTRI Accounting/Grants and Contracts Procurement/Supply Services Research Property Managment Research Security Services R.~P~~~t~lt~~na.~pfm~;P.G~->~~~~ GTRC Project File Other -----------------------------------------v y v v v N y v v N N FINAL PROGRESS REPORT Individual Postdoctoral National Research Service Award for R. Richard Plaskon S F32 HL07994-03 BI-4 Sponsored by F.L. Suddath Much of the training goals and research aims of the fellowship were satisfied. However, inadequacies in the application of available computational methods to accomplish the research aims necessitated the development of novel uses for the available methods. The amount of time devoted to this effort prevented the use of molecular dynamics and allowed only two enzymes to be studied. Nonetheless, valuable experience in the molecular modeling (excluding molecular dynamics) of serine proteases and their interactions with inhibitors was obtained. The quantum mechanical (QM) calculations performed resulted in much experience in using the semiempirical QM package MOP AC (QCPE, Indiana University). Many papers were read and discussions held on the inhibition of serine proteases and computational procedures of possible use in modeling serine protease inhibition as well as protein-ligand interactions. The research performed on porcine pancreatic elastase (PPE) resulted in the development of a method useful for the design of potent PPE inhibitors. The method produced results consistent with the potency of six 7-substituted 4-chloro-3-ethoxyisocoumarin inhibitors ofPPE and led to the synthesis of the most potent inhibitor of this class of PPE inhibitors. This novel inhibitor is as potent as predicted by the method. The molecular mechanics program, CHARMm of the Polygen Corp. (Waltham, MA 02254 ), used for the method provides a set of atomic point charges necessary for the electrostatic portion of the calculations. Inclusion of these charges produced results inconsistent with inhibitor potency. Only with charges derived from a MOP AC calculation is the method useful for the prediction of inhibitor potency toward PPE. A portion of the results with PPE have been published in the journal Proteins and another portion submitted for publication in Archives of Biochemistry and Biophysics. To determine if the method developed with PPE is suitable for the design of inhibitors for a medically important enzyme, inhibition of human leukocyte elastase (HLE) by 7-substituted 3-alkoxy-4-chloroisocoumarins was modeled. Unlike PPE, the x-ray structure of the native form of HLE is not known and only structures complexed with peptide and protein inhibitors are available. The inhibitors were removed and the method developed with PPE was performed. Results consistent with the potency of all three of the inhibitors tested were obtained. From these results, a fourth inhibitor is expected to be the best of the 7-substituted 4-chloro-3-ethoxyisocoumarin inhibitors of HLE. Publication of these results is planned. Publications (Current and Future) Plaskon, R.R., Kam, C.-M., Burgess, E.M., Powers, J.C., and Suddath, F.L. Michaelis Complexes of Porcine Pancreatic Elastase with 7-[(Alkylcarbamoyl)amino]-4-Chloro-3-Ethoxyisocoumarins: Translational Sampling of Inhibitor Position and Kinetic Measurements. (1992) Proteins 13, 141-151. Plaskon, R.R., Kam, C.-M., Kerrigan, J.E., Burgess, E.M., Powers, J.C., and Suddath, F.L. Inhibition of Porcine Pancreatic Elastase by 7-Substituted 4-Chloro-3-Ethoxyisocoumarins: Structural Characterisitics of Modeled Noncovalent Complexes Relate to the Measured Inhibition Kinetics. (1992) Archives of Biochemistry and Biophysics, submitted. Plaskon, R.R., Kam, C.-M., Burgess, E.M., Powers, J.C., and Suddath, F.L. Modeled Structural Characteristics Relate to the Inhibition of Human Leukocyte Elastase by 7-Substituted 3-Alkoxy-4-Chloroisocoumarins. (1992) Planned. R. RICHARD PLASKON Inventions and/or Patents None R. Richard Plaskon 5 F32 HL07994-03 Bl-4 June 26, 1992 

Molecular modeling of inhibitor-protease complexes

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Molecular modeling of inhibitor-protease complexes

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