Synthesis and evaluation of pyridyl analogs of L-735,524: Potent HIV-1 protease inhibitors

Dorsey, Bruce D.; McDaniel, Stacey L.; Levin, Rhonda B.; Vacca, Joseph P.; Darke, Paul L.; Zuga, Joan A.; Emini, Emilio A.; Schleif, William A.; Lin, Jiunn H.; Chen, I‐Wei; Holloway, M. Katharine; Anderson, Paul S.; Huff, Joel R.

doi:10.1016/s0960-894x(01)80592-8

“…Table illustrates attempts in this regard. Upon the basis of the previous success of [2,3- b ]- and [3,2- b ]thienothiophenes, the [2,3- b ]- and [3,2- b ]furopyridine moieties were incorporated into the S 3 pocket. Contrary to the thienothiophenes, the furopyridine ring contains a weakly basic nitrogen which should provide the target analogues with some aqueous solubility.…”

Section: Resultsmentioning

confidence: 99%

“…Previous work has described the design strategy which led to the introduction of the HAPA transition-state isostere and resulted in the identification of indinavir . The effects of placing large lipophilic heterocycles in the S 3 enzyme site in combination with a pyridyl P1‘ ligand (Chart ) has been described in a subsequent publication . This research resulted in the identification of L-748,496, a potent, selective, and orally bioavailable protease inhibitor with pharmacokinetic profiles in rats, dogs, and monkeys comparable to those with indinavir.…”

Section: Design Rationalementioning

confidence: 99%

Identification of MK-944a: A Second Clinical Candidate from the Hydroxylaminepentanamide Isostere Series of HIV Protease Inhibitors

Dorsey

¹

,

McDonough

²

,

McDaniel

³

et al. 2000

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Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

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“…Because the transition state of an enzymatic reaction is energetically stabilized for catalytic activity, the inhibitor molecule that mimics the transition state structure of the enzyme's wild-type substrate is expected to be bound to the enzyme more strongly than the substrate in the reactant and product states. An inhibitor, Indinavir (Figures 1 and 2), is one of such transition state analogs [7][8][9][10][11][12][13][14][15]. Indinavir possesses an sp 3 secondary alcohol structure, instead of an sp 2 carbonyl one in the wild-type peptide substrate, at the cleavage site in the vicinity 4 of the catalytic Asp25 groups.…”

Section: Introductionmentioning

confidence: 99%

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV-1 protease

Taguchi

¹

,

Oyama

²

,

Kaneso

³

et al. 2022

Preprint

0

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Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

show abstract

“…Because the transition state of an enzymatic reaction is energetically stabilized for catalytic activity, the inhibitor molecule that mimics the transition state structure of the enzyme's native substrate is expected to be bound to the enzyme more strongly than the substrate in the reactant and product states. An inhibitor, Indinavir (Figures 1 and 2), is one of such transition state analogs [7][8][9][10][11][12][13][14]. Indinavir possesses an sp 3 secondary alcohol structure, instead of an sp 2 carbonyl one in the native peptide substrate, at the cleavage site in the vicinity of the catalytic Asp25 groups.…”

Section: Introductionmentioning

confidence: 99%

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

Taguchi

¹

,

Oyama

²

,

Kaneso

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

show abstract

Synthesis and evaluation of pyridyl analogs of L-735,524: Potent HIV-1 protease inhibitors

Cited by 21 publications

References 20 publications

Identification of MK-944a: A Second Clinical Candidate from the Hydroxylaminepentanamide Isostere Series of HIV Protease Inhibitors

Identification of MK-944a: A Second Clinical Candidate from the Hydroxylaminepentanamide Isostere Series of HIV Protease Inhibitors

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV-1 protease

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

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