Human immunodeficiency virus 1 (HIV-1) protease {is a|is really a|is actually a|can be a|is often a|is usually a} homo-dimeric aspartic protease {essential|important|crucial|vital|necessary|critical} for replication of HIV. The HIV-1 protease {is a|is really a|is actually a|can be a|is often a|is usually a} target protein in drug discovery for antiretroviral therapy, and {various|numerous|different|a variety of|several|many} inhibitor molecules of transition state analog {were|had been|have been} {developed|created}. {However|Nevertheless|Nonetheless|Even so|On the other hand|Having said that}, {serious|severe|significant|critical|really serious} drug-resistant mutants have emerged. For understanding molecular mechanism {of the|from the|in the|on the|with the|of your} drug-resistance, {accurate|correct|precise} examination {of the|from the|in the|on the|with the|of your} impacts {of the|from the|in the|on the|with the|of your} mutations on ligand binding {as well|also|too|at the same time} as enzymatic activity is {necessary|essential|required|needed|important|vital}. {Here|Right here}, we present a molecular simulation study {on the|around the} ligand binding of Indinavir, a potent transition state analog inhibitor, {to the|towards the|for the} native protein {and a|along with a|as well as a|plus a|and also a|in addition to a} V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) {free|totally free|free of charge|cost-free|absolutely free|no cost} {energy|power} optimization {technique|method|approach|strategy} which combines {highly|extremely|very|hugely} {accurate|correct|precise} QM description {of the|from the|in the|on the|with the|of your} ligand molecule and its interaction with statistically ample conformational sampling of MM protein {environment|atmosphere} by long-time molecular dynamics simulations. {Through|Via|By means of|By way of} {free|totally free|free of charge|cost-free|absolutely free|no cost} {energy|power} calculations of protonation states of catalytic groups {at the|in the} binding pocket and of ligand binding affinity {changes|modifications|adjustments|alterations} upon the mutations, we {successfully|effectively} reproduced the experimentally observed {significant|substantial|considerable|important} reduction {of the|from the|in the|on the|with the|of your} 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|via|by means of|by way of} direct quantitative comparison of ligand binding and enzymatic reaction {with the|using the|with all the|together with the} {same|exact same|identical|very same|similar} accuracy. Sucrose monolaurate site 1-Ethynyl-3,5-difluorobenzene In stock PMID:26780211
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