Computer-aided synthesis of dapsone-phytochemical conjugates against dapsone-resistant Mycobacterium leprae

Abstract

Leprosy continues to be the belligerent public health hazard for the causation of high disability and eventual morbidity cases with stable prevalence rates, even with treatment by the on-going multidrug therapy (MDT). Today, dapsone (DDS) resistance has led to fear of leprosy in more unfortunate people of certain developing countries. Herein, DDS was chemically conjugated with five phytochemicals independently as dapsone-phytochemical conjugates (DPCs) based on azo-coupling reaction. Possible biological activities were verified with computational chemistry and quantum mechanics by molecular dynamics simulation program before chemical synthesis and spectral characterizations viz., proton-HNMR, FTIR, UV and LC-MS. The in vivo antileprosy activity was monitored using the 'mouse-foot-pad propagation method', with WHO recommended concentration 0.01% mg/kg each DPC for 12 weeks, and the host-toxicity testing of the active DPC4 was seen in cultured-human-lymphocytes in vitro. One-log bacilli cells in DDS-resistant infected mice footpads decreased by the DPC4, and no bacilli were found in the DDS-sensitive mice hind pads. Additionally, the in vitro host toxicity study also confirmed that the DCP4 up to 5,000 mg/L level was safety for oral administration, since a minor number of dead cells were found in red color under a fluorescent microscope. Several advanced bioinformatics tools could help locate the potential chemical entity, thereby reducing the time and resources required for in vitro and in vitro tests. DPC4 could be used in place of DDS in MDT, evidenced from in vivo antileprosy activity and in vitro host toxicity study.

Molecular mechanisms of underlying genetic factors and associated mutations for drug resistance in Mycobacterium tuberculosis

“…Thus, an ideal drug candidate should manage both activity and toxicity with pharmacokinetic properties for more success in drug validation modules. Strategically, several advanced chemical conjugation/drug modification through medicinal chemistry protocol and nanoparticle/nanocarrier formulations has been adopted for the utilization of more natural products in anti-TB drug development [78][79][80]. Nevertheless, long-term investment, administrative commitment, interior geographical support and scientific endeavour will be playing the crucial factors for a sustainable TB-free society.…”

Metabolic Diversity and Therapeutic Potential of Holarrhena pubescens: An Important Ethnomedicinal Plant

“…A similar docking approach was also used by Cheenpracha et al, taking mokluangin A-C and antidysentericine as ligand, and the crystallographic structure of AChE reported from Electrophorus electricus (PDB ID: 1C2B) [ 145 ]. Similarly, using information from previous studies, six different biological activities of conessine such as antibacterial, anti-CNS, antidiabetic, antifungal, anti-inflammatory and antimalarial were analyzed through a blind docking approach [ 147 , 148 ]. To find out more molecular details on the binding mode of this steroid-alkaloid moiety to the presumptive molecular targets ( Figure 5 ).…”

“…Thus, a docking study may a cost-effective computational analysis to help understand different biological activities in the form of binding energy and possible molecular interaction-cum-mode of inhibition. Nowadays, molecular docking is also a useful tool in drug development to identify potential hit and better lead compounds, as well as insights into their mode of action [ 145 , 148 ].…”

Molecular docking-simulation edge assessment of potential and less-toxic ‘anti- HIV-drug and phyto-flavonoid’ combination against COVID-19

“…Someway, non-conventional therapy using Ayurveda and TCM regimens gives some productive outputs against SARS-CoV-2 from several recent reports 26, 27, 28, 29. Concomitantly, the computer-aided drug development (CADD) program is a cost-effective and time saving and decisive method in ongoing drug discovery modules. The CADD program could be a promising endeavor in newer anti-CoV drug development using lead-drug candidates than the traditional hit-and-trial selection process 30-33. Mainly, the high-throughput screening to locate active most chemical moieties based on binding energy or docking scores before synthesis and expensive experimental validation are directly influencing the reduction of cost of medicine in the later stage 42,53,54. Furthermore, the backbone RMSDs, Cα-RMSF, Rg-plot, and intermolecular H-bonds analyses through all-atom MDS provide more productive results with more thermodynamic features as well as, underlying kinetics behavior of protein-ligand docking complexes 42, 53, 54. Des.…”

“…Mainly, the viral protease is a prudent drug target, as the M pro plays a pivotal enzyme for viral genome replication 30, 32, 39, 40. Thus, this might be a novel idea in current anti-CoV drug development by utilizing the potent natural product along with an anti-HIV drug feasibly and cost-effectively. tipranavir-LPRP-Et-97543 were performed 42,43. Generated ten interaction poses for each ligand, the most effective pose was selected based on its binding energy/ docking score and ligand efficacy 41-43. Further, the most effective docking complexes were selected for stability check by molecular dynamic simulation (MDS) study.…”