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Open Access September 20, 2022 Endnote/Zotero/Mendeley (RIS) BibTeX

Drug-Receptor Interaction of Peptidic HIV-1 Protease: Polar Effect-II

Abstract Klopman described the chemical reaction of metal ions and base ions in term of softness, En and Em, respectively. By simple modification of known methods, Singh et al. made it applicable for neutral Lewis acids (transition metal salts) and bases (organic molecules) and also extended its application to biological systems for site selectivity [...] Read more.
Klopman described the chemical reaction of metal ions and base ions in term of softness, En and Em, respectively. By simple modification of known methods, Singh et al. made it applicable for neutral Lewis acids (transition metal salts) and bases (organic molecules) and also extended its application to biological systems for site selectivity and to explain reaction mechanism (markovnikov and anti-markovnikov rule), ligand-receptor interaction of testosterones, estrogens and tetrahydroimidazobenzodiazepinone. In this study effective atomic softness En(eff) and Em(eff), and their change ΔEnm have been used for site selectivity and polar interaction between 51 peptidic HIV-1 protease inhibitors and receptor amino acids. ΔEnm values derived from drug-receptor interaction show that when one moiety on receptor behaves as nucleophile (O of valine amino acid) at the same time maximum electrophilic site of the drug (C-atom of the maximum En(eff) value) orient itself to come close the respective site and make maximum interaction, while when another moiety on receptor behaves as electrophilic site (C of isoleucine amino acid), at the same time maximum nucleophilic site of the drug (O-atom of the maximum Em(eff) value) also orient itself to come close the respective site and make maximum interaction.
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Open Access August 31, 2022 Endnote/Zotero/Mendeley (RIS) BibTeX

Extended Rule of Five and Prediction of Biological Activity of peptidic HIV-1-PR Inhibitors

Abstract In this research work, we have applied “Lipinski’s RO5” for pharmacokinetics (PK) study and to predict the activity of peptidic HIV-1 protease inhibitors. Peptidic HIV-1-PRIs have been taken from literature with their observed biological activities (OBAs) in term of IC50. The logarithms of the inverse of IC50 have been used as biological end point o(log1/C) in the study. For calculation of [...] Read more.
In this research work, we have applied “Lipinski’s RO5” for pharmacokinetics (PK) study and to predict the activity of peptidic HIV-1 protease inhibitors. Peptidic HIV-1-PRIs have been taken from literature with their observed biological activities (OBAs) in term of IC50. The logarithms of the inverse of IC50 have been used as biological end point o(log1/C) in the study. For calculation of physicochemical parameters, the molecular modeling and geometry optimization of all the derivatives have been carried out with CAChe Pro software using semiempirical PM3 method. Prediction of the biological activity of the inhibitors has shown that the best QSAR model is constructed from pharmacokinetic properties, molecular weight and hydrogen bond acceptor. This also proved that these properties play important role to describe the PKs of the drugs. On the basis of the derived models one can build up a theoretical basis to access the biological activity of the compounds of the same series.
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Open Access September 04, 2022 Endnote/Zotero/Mendeley (RIS) BibTeX

Drug-Receptor Interaction of Peptidic HIV-1 Protease: The Hydrophobic Effect-I

Abstract When a drug interacts with its receptor, the nonpolar substituent of drug and receptor proteins attract each other because they have opposite magnitude with respect to each other. X-rays structure studies reflected that the S2/S2’ pocket in HIV-1 protease enzyme are essentially hydrophobic. The residues that make up these pockets are Val-32, Ile-47, Ile-50, and Ile-84 in each monomeric [...] Read more.
When a drug interacts with its receptor, the nonpolar substituent of drug and receptor proteins attract each other because they have opposite magnitude with respect to each other. X-rays structure studies reflected that the S2/S2’ pocket in HIV-1 protease enzyme are essentially hydrophobic. The residues that make up these pockets are Val-32, Ile-47, Ile-50, and Ile-84 in each monomeric polypeptidic unit of the protease enzyme. Δπdr and ΔSASAdr have been used to measure the extent of hydrophobic interaction between peptidic protease inhibitors and receptor proteins (binding site: valine‒isoleucine; and catalytic site: glycine‒aspartic acid‒threonine) on the HIV-1 protease enzyme. For measurement of hydrophobic interaction, the molecular modeling and geometry optimization of all the inhibitors and the receptor amino acids have been carried out with CAChe Pro software by opting semiempirical PM3 methods. Log P was calculated using the atom-typing scheme of Ghose and Crippen, while solvent accessible surface area by conductor likes screening model. πd, πr, SASASd and SASASr well describe the hydrophobicities of the substituents and play the effective role for site selectivity for interaction of the drug with the receptor. Comparative study of values of Δπdr and ΔSASAdr show the order of hydrophobic interaction with respect to amino acids: Asp > Thr > Val > Ile and Thr > Val > Asp > Ile, respectively. Further, comparative study of the values of (ΣΔπdr)binding-site, (ΣΔπdr)catalytic-site, (ΣΔSASAdr)binding-site, (ΣΔSASAdr)catalytic-site shows that peptidic HIV-1-PRIs interact with binding site rather than catalytic site as binding site have lower value of ΣΔπdr and ΣΔSASAdr. Among the binding site, Val has maximum interaction than Ile, as it has lower vale of Δπdr and ΔSASAdr.
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Keyword:  Pashupati Prasad Singh

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