Inhibitor designing, virtual screening, and docking studies for methyltransferase: A potential target against dengue virus

Abstract

Aim:Aim of this work was to design and identify some S-adenosyl-L-homocysteine (SAH) analogs as inhibitors of S-adenosyl-L-methionine-dependent methyltransferase (MTase) protein using computational approaches.Introduction:According to the current scenario the dengue has been a global burden. The people are being killed by dengue virus in an abundant number. Despite of lot of research being going on dengue worldwide, there is no single drug which can kill its virus. This creates an urge for new drug target identification and designing. MTase has been reported as an effective target against dengue virus as it catalyzes an essential step in methylation and capping of viral RNA for viral replication.Materials and Methods:The crystal structure of MTase in complex with SAH was used for designing new analogs of SAH. SAH analogs designed were analyzed on the basis of docking, ADMET, and toxicity analysis done using Discovery Studio 3.5.Results:Seventeen analogs found noncarcinogenic, nonmutagenic, as well as good ADMET properties and good drug-like profile.Conclusion:These SAH analogs, inhibitors of MTase may act as drugs against dengue virus. Further synthesis and biological testing against dengue virus is under observation.

Ligand-based Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies for Discovery of Potential Topoisomerase I Inhibitors

“…Based on the toxicity profiling, ZINC68997780, ZINC38550809, and ZINC15018994 were assessed by ADMET studies in Discovery Studio client [24]. The three molecules were further analyzed by molecular dynamics (MD) studies to determine ligand binding stability in the Top1-DNA cleavage complex.…”

Novel series of 1,2,4-trioxane derivatives as antimalarial agents

“…The compounds were prepared using the prepare ligand module of the DS which includes assigning bond orders, generating various tautomers, ring conformations and stereochemistries. All the conformations generated were then energetically minimised by a single step Steepest Descent method using CHARMM (Chemistry at HARvard Macromolecular Mechanics, Cambridge, MA) Force Field with 5000 iterations and a minimum root mean square (RMS) gradient of 0.01 kcal/mol/Å 23 .…”

“…Subsequently, the 3D structure of protein was optimised by energy minimisation using CHARMM Force Field. It was done in two steps to remove the bad steric clashes using Steepest Descent and Conjugate Gradient methods for 5000 steps at RMS gradients of 0.01 and 0.05 kcal/mol/Å, respectively 23 .…”

ADMET profile and virtual screening of plant and microbial natural metabolites as SARS-CoV-2 S1 glycoprotein receptor binding domain and main protease inhibitors

“…However, binding affinity in some of the test compounds (putaminoxins B and D, jasmonic acid, jasmonic acid methyl ester) against the active site of the M pro enzyme observed to be significant as compared to the penciclovir. Libdock has been widely used as a tool for virtual screening of small molecules against protein or enzyme targets ( Rao et al, 2007 ; Singh et al, 2016 ; Alam and Khan 2018 ). Libdock score which is a cumulative count of all non covalent interactions including the van der Waals has been adopted in many instances for determining the binding affinity (Zhou et al, 2016; Kang et al, 2018 ).…”

“…A virtual screening of the selected compounds including a reference antiviral drug penciclovir (PubChem CID: 135398748) ( Razonable 2011 ) was carried out using the DS Libdock, a rigid based program that calculates hotspots for the receptor with placing a grid into the binding site, as well as using polar and apolar probes ( Singh et al, 2016 ; Kang et al, 2018 ). The libdock score determines the binding affinity of the ligands towards a receptor, and is a cumulative count of van der Waals forces, H-bonds, pi interactions and other parameters.…”