Lokesh Kori

Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain. Current treatments provide limited symptomatic relief without halting disease progression. A multi-targeting approach has shown potential benefits in treating neurodegenerative diseases. In this study, we employed in silico approaches to explore the COCONUT natural products database and identify novel drug candidates with multi-target potential against relevant Parkinson's disease targets. QSAR models were developed to screen for potential bioactive molecules, followed by a hybrid virtual screening approach involving pharmacophore modeling and molecular docking against MAO-B, AA_2AR, and NMDAR. ADME evaluation was performed to assess drug-like properties. Our findings revealed 22 candidates that exhibited the desired pharmacophoric features. Particularly, two compounds: CNP0121426 and CNP0242698 exhibited remarkable binding affinities, with energies lower than -10 kcal/mol and promising interaction profiles with the chosen targets. Furthermore, all the ligands displayed desirable pharmacokinetic properties for brain-targeted drugs. Lastly, molecular dynamics simulations were conducted on the lead candidates, belonging to the dihydrochalcone and curcuminoid class, to evaluate their stability over a 100 ns timeframe and compare their dynamics with reference complexes. Our findings revealed the curcuminoid CNP0242698 to have an overall better stability with the three targets compared to the dihydrochalcone, despite the high ligand RMSD, the curcuminoid CNP0242698 showed better protein stability, implying ligand exploration of different orientations. Similarly, AA_2AR exhibited higher stability with CNP0242698 compared to the reference complex, despite the high initial ligand RMSD due to the bulkier active site. In NMDAR, CNP0242698 displayed good stability and less fluctuations implying a more restricted conformation within the smaller active site of NMDAR. These results may serve as lead compounds for the development and optimization of natural products as multi-target disease-modifying natural remedies for Parkinson's disease patients. However, experimental assays remain necessary to validate these findings.Communicated by Ramaswamy H. Sarma.

Background India is on track to eliminate malaria by 2030 but emerging resistance to the first-line antimalarials is a recognized threat. As Artesunate+Sulfadoxine-Pyrimethamine (AS+SP) is the drug-of-choice for uncomplicated P. falciparum malaria in most of India, it becomes evident to systematically monitor the validated mutations in Pfdhfr and Pfdhps genes across India. No systematic and robust countrywide surveillance has been reported for these parameters in India. Methods We included studies that reported data on SP-resistance markers in P. falciparum across India from 2008. Five major databases were exhaustively searched. Individual and pooled prevalence estimates of mutations were obtained through random- and fixed-effect models. The study is registered with PROSPERO (CRD42021236012). Results A total of 37 publications with data from 80 districts, 21 states and 3 UTs were included. The two PfDHFR mutations, C59R and S108N were the most prevalent mutations and appear to be stabilized/fixed. Although rarest overall, the prevalence of I164L was observed to be as high as 32%. The PfDHFR double mutants were the most prevalent overall. The prevalence of triple and quadruple mutations was 6% and 5%, respectively which is an area of immediate concern. For PfDHPS, the most prevalent mutation was A437G. For PfDHFR/PfDHPS quintuple and sextuple mutations, it was observed that despite a low overall prevalence of these mutations, some areas are critical for surveillance. Conclusion The analysis brings forward the SP-resistance hot spots and emphasizes critical gaps, and challenges, and suggests focal and local malaria genetic surveillance (including drug resistance markers) till malaria is eliminated. Key points This manuscript concludes that currently used first-line drugs for P. falciparum malaria, particularly sulfadoxine-pyrimethamine, have a high likelihood of failing in near future. Although currently effective, the evidence is backed by molecular meta-analyses data on drug resistance markers in India. The policy makers and program managers may use this robust data to decide whether it is time to change these currently used anti-malarials in India before it is too late. It also identifies certain hot spots for continuous genetic monitoring of the molecular markers for timely actions.