Browsing by Author "Amit Jayaswal"

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Evaluation of binding of potential ADMET/tox screened saquinavir analogues for inhibition of HIV-protease via molecular dynamics and binding free energy calculations
(Taylor and Francis Ltd., 2022) Amit Jayaswal; Ekta Pathak; Hirdyesh Mishra; Kavita Shah
Developing novel drug molecules against HIV is a scientific quest necessitated by development of drug resistance against used drugs. We report comparative results of molecular dynamics simulation studies on 11 structural analogues of Saquinavir (SQV)–against HIV-protease that were earlier examined for pharmacodynamic and pharmacokinetic properties. We reported analogues S1, S5 and S8 to qualify the ADMET criterion and may be considered as potential lead molecules. In this study the designed molecules were successively docked with native HIV-protease at AutoDock. Docking scores established relative goodness of the 11 analogues against the benchmark for Saquinavir. The docked complexes were subjected to molecular dynamics simulation studies using GROMACS 4.6.2. Four parameters viz. H-bonding, RMSD, Binding energy and Protein–Ligand Distance were used for comparative analyses of the analogues relative to Saquinavir. The comparison and analysis of the results are indicative that analogues S8, S9 and S1 are promising candidates among all the analogues studied. From our earlier work and present study it is evident that among the three S8 and S1 qualify the ADMET criterion and between S1 and S8, the analogue S8 shows more target efficacy and specificity over S1 and have better molecular dynamics simulation results. Thus, of the 11 de novo Saquinavir analogues, the S8 appears to be the most promising candidate as lead molecule for HIV-protease inhibitor and is best suited for testing under biological system. Further validation of the proposed lead molecules through wet lab studies involving antiviral assays however is required. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
Examining pharmacodynamic and pharmacokinetic properties of eleven analogues of saquinavir for HIV protease inhibition
(Springer-Verlag Wien, 2019) Amit Jayaswal; Hirdyesh Mishra; Ankita Mishra; Kavita Shah
HIV is one of the most lethal viral diseases in the human population. Patients often suffer from drug resistance, which hampers HIV therapy. Eleven different structural analogues of saquinavir (SQV), designed using ChemSketch™ and named S1 through S11, were compared with SQV with respect to their pharmacodynamic and pharmacokinetic properties. Pharmacokinetic predictions were carried out using AutoDock, and molecular docking between macromolecule HIV protease (PDB ID: 3IXO) and analogues S1 – S11 as ligands was performed. Analogues S1, S3, S4, S9 and S11 had lower binding scores when compared with saquinavir, whereas that of analogue S5 was similar. Pharmacokinetic predictions made using ACDilab2, including the Lipinski profile, general physical features, absorption, distribution, metabolism and excretion parameters, and toxicity values, for the eleven analogues and SQV suggested that S1 and S5 are pharmacodynamically and pharmacokinetically robust molecules that could be developed and established as lead molecules after in vitro and in vivo studies. © 2019, Springer-Verlag GmbH Austria, part of Springer Nature.
Examining structural analogs of elvitegravir as potential inhibitors of HIV-1 integrase
(Springer-Verlag Wien, 2014) Kavita Shah; Saumya Gupta; Hirdyesh Mishra; Prashant K. Sharma; Amit Jayaswal
Acquired immunodeficiency syndrome (AIDS) is a major health problem in many parts of the world. The human immunodeficiency virus-1 integrase (HIV-1 IN) enzyme has been targeted in HIV patients for therapy. Several integrase inhibitors have been reported, but only elvitegravir (EVG), a new-generation drug, is clinically approved for HIV treatment. In the present work, we investigated two structural analogs of EVG as potential inhibitors of the target molecule, HIV-1 IN. The ligand binding site on HIV-1 IN was identified using Q-SiteFinder, and the HIV-1 IN protein was docked with ligand (EVG and/or analogs) using AutoDock 4. The results suggest that Lys173, Thr125, and His171 are involved in enzyme-substrate binding through hydrogen bonds. Single mutations carried out at Lys173, viz. Lys173Leu (polar > nonpolar) and Lys173Gln (polar > polar), in chain B using PyMOL showed the mutants to have lower binding energy when docked with analog 2, suggesting it to be more stable than analog 1. In conclusion, the mutant HIV-1 IN can bind EVG and its analogs. The physicochemical and pharmacokinetic parameters also show analog 2 to be a promising molecule that can be developed as an alternative to EVG to help overcome the problem of drug resistance by HIV to this inhibitor. Analog 2 may be used as an HIV-1 IN inhibitor with similar potential to that of EVG. Further validation through wet-lab studies, however, is required for future applications. © 2014 Springer-Verlag Wien.
Nitrogen fertilizer-induced spatial variation in the size of methane oxidizing bacterial population in rainfed rice cultivars
(2012) Bharati Singh; Deepmala Katiyar; Durg Vijay Singh; Amit Jayaswal
This study was conducted to investigate the effect of N fertilization on methane oxidizing bacteria that lead to changes in the microbial communities in rice agroecosystems. Variation in MOB population size due to rice varieties of three different soil type bare, bulk and rhizosphere was investigated in rainfed rice NDR-97 (Narendra-97), Pant Dhan-12 and Vanaprabha. The growth variables (shoot biomass and root biomass) were higher in fertilized plots than unfertilized plots. The ammonium-N, nitrate-N was higher in fertilized plot than unfertilized plots. There were significant differences in MOB population size during the study (p<0.05). The highest MOB bacterial population was found in rhizospheric soils. So that, MOB bacterial population range between 19.2xlO6 to 70.54xl06 cells g1 dry across soil type of varieties and treatment. N-fertilization reduces population size of MOB. Thus the result suggests that MOB population size were varied by different soil type and soil fertilization. This study showed significant impact of N-fertilization on MOB population. © 2012 Knowledgia Review, Malaysia.