Structure-based design of parasitic protease inhibitors

Rongshi Li, Xiaowu Chen, Baoqing Gong, Paul M. Selzer, Zhe Li, Eugene Davidson, Gary Kurzban, Robert E. Miller, Edwin O. Nuzum, James H. McKerrow, Robert J. Fletterick, Sarah A. Gillmor, Charles S. Craik, Irwin D. Kuntz, Fred E. Cohen, George L. Kenyon

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compound enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthylmethylene)hydrazide (1) [Ring, C.S.; Sun, E.; McKerow, J.K.; Lee, G.; Rosenthal, P.J., Kuntz, I.D.; Cohen, F.E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC 50 6 μM) and the organism in vitro as judged by hypoxanthine. uptake (IC 50 7 μM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC 50 150 nM) and chalcones (IC 50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 Å, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC 50 600 μM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.

Original languageEnglish (US)
Pages (from-to)1421-1427
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume4
Issue number9
DOIs
StatePublished - Jan 1 1996

Fingerprint

Protease Inhibitors
Cysteine Proteases
Chloroquine
Enzymes
Pharmaceutical Preparations
Chalcones
Computational chemistry
Enzyme inhibition
Trophozoites
Parasitic Diseases
Hypoxanthine
Papain
Pharmaceutical Chemistry
Enzyme Inhibitors
Solar System
Life Cycle Stages
Sun
Malaria
Communicable Diseases
Life cycle

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Li, R., Chen, X., Gong, B., Selzer, P. M., Li, Z., Davidson, E., ... Kenyon, G. L. (1996). Structure-based design of parasitic protease inhibitors. Bioorganic and Medicinal Chemistry, 4(9), 1421-1427. https://doi.org/10.1016/0968-0896(96)00136-8

Structure-based design of parasitic protease inhibitors. / Li, Rongshi; Chen, Xiaowu; Gong, Baoqing; Selzer, Paul M.; Li, Zhe; Davidson, Eugene; Kurzban, Gary; Miller, Robert E.; Nuzum, Edwin O.; McKerrow, James H.; Fletterick, Robert J.; Gillmor, Sarah A.; Craik, Charles S.; Kuntz, Irwin D.; Cohen, Fred E.; Kenyon, George L.

In: Bioorganic and Medicinal Chemistry, Vol. 4, No. 9, 01.01.1996, p. 1421-1427.

Research output: Contribution to journalArticle

Li, R, Chen, X, Gong, B, Selzer, PM, Li, Z, Davidson, E, Kurzban, G, Miller, RE, Nuzum, EO, McKerrow, JH, Fletterick, RJ, Gillmor, SA, Craik, CS, Kuntz, ID, Cohen, FE & Kenyon, GL 1996, 'Structure-based design of parasitic protease inhibitors', Bioorganic and Medicinal Chemistry, vol. 4, no. 9, pp. 1421-1427. https://doi.org/10.1016/0968-0896(96)00136-8
Li, Rongshi ; Chen, Xiaowu ; Gong, Baoqing ; Selzer, Paul M. ; Li, Zhe ; Davidson, Eugene ; Kurzban, Gary ; Miller, Robert E. ; Nuzum, Edwin O. ; McKerrow, James H. ; Fletterick, Robert J. ; Gillmor, Sarah A. ; Craik, Charles S. ; Kuntz, Irwin D. ; Cohen, Fred E. ; Kenyon, George L. / Structure-based design of parasitic protease inhibitors. In: Bioorganic and Medicinal Chemistry. 1996 ; Vol. 4, No. 9. pp. 1421-1427.
@article{addca4dccb8641ce90d3d106261ec13f,
title = "Structure-based design of parasitic protease inhibitors",
abstract = "To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compound enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthylmethylene)hydrazide (1) [Ring, C.S.; Sun, E.; McKerow, J.K.; Lee, G.; Rosenthal, P.J., Kuntz, I.D.; Cohen, F.E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC 50 6 μM) and the organism in vitro as judged by hypoxanthine. uptake (IC 50 7 μM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC 50 150 nM) and chalcones (IC 50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 {\AA}, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC 50 600 μM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.",
author = "Rongshi Li and Xiaowu Chen and Baoqing Gong and Selzer, {Paul M.} and Zhe Li and Eugene Davidson and Gary Kurzban and Miller, {Robert E.} and Nuzum, {Edwin O.} and McKerrow, {James H.} and Fletterick, {Robert J.} and Gillmor, {Sarah A.} and Craik, {Charles S.} and Kuntz, {Irwin D.} and Cohen, {Fred E.} and Kenyon, {George L.}",
year = "1996",
month = "1",
day = "1",
doi = "10.1016/0968-0896(96)00136-8",
language = "English (US)",
volume = "4",
pages = "1421--1427",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "9",

}

TY - JOUR

T1 - Structure-based design of parasitic protease inhibitors

AU - Li, Rongshi

AU - Chen, Xiaowu

AU - Gong, Baoqing

AU - Selzer, Paul M.

AU - Li, Zhe

AU - Davidson, Eugene

AU - Kurzban, Gary

AU - Miller, Robert E.

AU - Nuzum, Edwin O.

AU - McKerrow, James H.

AU - Fletterick, Robert J.

AU - Gillmor, Sarah A.

AU - Craik, Charles S.

AU - Kuntz, Irwin D.

AU - Cohen, Fred E.

AU - Kenyon, George L.

PY - 1996/1/1

Y1 - 1996/1/1

N2 - To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compound enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthylmethylene)hydrazide (1) [Ring, C.S.; Sun, E.; McKerow, J.K.; Lee, G.; Rosenthal, P.J., Kuntz, I.D.; Cohen, F.E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC 50 6 μM) and the organism in vitro as judged by hypoxanthine. uptake (IC 50 7 μM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC 50 150 nM) and chalcones (IC 50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 Å, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC 50 600 μM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.

AB - To streamline the preclinical phase of pharmaceutical development, we have explored the utility of structural data on the molecular target and synergy between computational and medicinal chemistry. We have concentrated on parasitic infectious diseases with a particular emphasis on the development of specific noncovalent inhibitors of proteases that play a key role in the parasites' life cycles. Frequently, the structure of the enzyme target of pharmaceutical interest is not available. In this setting we have modeled the structure of the relevant enzyme by virtue of its sequence similarity with proteins of known structure. For example, we have constructed a homology-based model of falcipain, the trophozoite cysteine protease, and used the computational ligand identification algorithm DOCK to identify in compound enzyme inhibitors including oxalic bis(2-hydroxy-1-naphthylmethylene)hydrazide (1) [Ring, C.S.; Sun, E.; McKerow, J.K.; Lee, G.; Rosenthal, P.J., Kuntz, I.D.; Cohen, F.E., Proc. Natl Acad. Sci. U.S.A. 1993, 90, 3583]. Compound 1 inhibits falcipain (IC 50 6 μM) and the organism in vitro as judged by hypoxanthine. uptake (IC 50 7 μM). Following this lead, to date, we have identified potent bis arylacylhydrazides (IC 50 150 nM) and chalcones (IC 50 200 nM) that are active against both chloroquine-sensitive and chloroquine-resistant strains of malaria. In a second example, cruzain, the crystallographically determined structure of a papain-like cysteine protease, resolved to 2.35 Å, was available. Aided by DOCK, we have identified a family of bis-arylacylhydrazides that are potent inhibitors of cruzain (IC 50 600 μM). These compounds represent useful leads for pharmaceutical development over strict enzyme inhibition criteria in a structure-based design program.

UR - http://www.scopus.com/inward/record.url?scp=16044363907&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16044363907&partnerID=8YFLogxK

U2 - 10.1016/0968-0896(96)00136-8

DO - 10.1016/0968-0896(96)00136-8

M3 - Article

VL - 4

SP - 1421

EP - 1427

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 9

ER -