Molecular Simulation For HIV-1Rt/POMs And SARS-CoV Main Protease/POMs Enzyme-inhibitor Interaction

AIDS is a disease caused by the HIV virus that has greatly affected the world, thus a greatdeal of chemistry has been focused on the goal of developing a method of treatment for thisillness. HIV peptide chain is broken into three functional enzymes in its active form: protease,integrase, and reverse transcriptase. Many well-known inhibitor strategies have chosen tofocus on the reverse transcriptase to develop treatments. These inhibitors alone have provedinsufficient since the virus has been able to mutate to other, more stable, forms. This caused ashift in strategies to protease inhibitors with the theory that being able to stop the virus beforeit can be activated would be the best method.Recently, much attention has been paid to the Ti-containing α-Keggin polyoxometalates(POMs). They have been proved with properties of both anti-tumor and anti-HIV. Amongvarious POMs, the di-Ti-substituted α-Keggin type structure [α-PTi2 W10O40]7-isomers are ofparticular interest, because they have high catalytic activity and capability of inhibitingreplication of several types of DNA or RNA viruses. It is very significant to explore theinhibition potency of α-Keggin POMs to HIV-1 CoV as well as SARS CoV. And above all, itis of great significance to explore molecular mechanism and molecular dynamics mechanismwhen studying problems related to POMs. In this investigation, Binding energy wascompared, hydrogen bonds formation and electrostatic interaction were analyzed, active sitekey residues and the interaction mechanism were also discussed at the molecular level. Thepotential anti-virus activity of the POMs [α-PTi2W10 O40]7-isomers was investigated bymolecular modeling method.The investigations concerned in this paper are manily about:1. Ti-containing polyoxometalates (POMs) of the Keggin class [α-PTi2W10 O40]7-inhibitHIV-1 reverse transcriptase (HIV-1 Rt) at a novel site by a new mode based on kinetics,binding, and molecular modeling studies. Molecular dynamics (MD) simulation is performedbased on the crystal structure of dimer of HIV-1Rt using Affinity/Insight II module. Analysesincluding molecular surface electrostatic potential and atomic point charge dispersion of keyresidues as well as molecular steric conformation were performed to explore possible bindingmold. The kinetics and binding studies, strongly suggest that POMs function not by binding tothe NRTI or the NNRTI active site of HIV-1Rt, but by binding to a novel site between thedimmer interface of HIV-1Rt. Electrostatic energy is vital elements for enzyme-POMsinteraction. Binding energy analysis is consistent with the steric geometric as well as thecharge constraints of the two molecules. The interaction may corrupt the dimer structure ofHIV-1 Rt so that it no longer proper for performing relative functions, or hindered/ orprevented flap movement so that the dimmer may not be able to close upon its substrate. Theresults illustrate a viable alternative explanation of inhibition potent between POMs onHIV-1Rt and provide a chemical insight for anti-AIDS drug design.2. Ti-containing α-Keggin polyoxometalates (POMs) have been proved with properties of both anti-tumorand anti-HIV. The potential anti-SARS activity of the POMs [α-PTi2W10 O40]7-isomers was investigated inthis paper by molecular modeling method. The SARS 3c like protease, namely the SARS 3CLpro is the keyfunction protease for virus replication as well as transcription and thus can be taken as one of the keytargets for anti-SARS drug design. The results show that POMs bind with 3CLpro at the enzyme catalystwith high affinity;for the POMs/3CLpro complex, the OTi2 in POMs is the vital element for electrostaticinteraction, and the electrostatic binding energy is strong enough to keep the complex stable.3. The kinetics and binding studies, conducted after the molecular modeling, are both in remarkableagreement with the modeling results as well as experiment results. Using a computer calculation andsimulation method we performed docking studies in a binary complex (enzyme–POMs) to proposetentatively possible binding site, consistent with the available biochemical results as well as with thegeometric and charge constraints of the two molecules. The results provide a chemical insight into theinteractions between POMs and HIV-1Rt, and provide insight for anti-AIDS drug design.