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- Malaria remains a significant global health problem; with the potential for developing resistance to conventional antimalarials justifying novel therapeutic approaches. This study investigates the potential of microalgal metabolites as dual-inhibitors of Plasmodium falciparum glutathione S-transferase (PfGST) and apical membrane antigen 1 (AMA1); two of the most important proteins in parasite survival and host cell invasion. By high-throughput molecular docking simulations; we studied binding energy distributions; conformational characteristics by principal component analysis; pharmacophoric and pharmacokinetic research with structure-activity relationships of its inhibitors. Our findings indicate various patterns of interactions: PfGST exhibits a unimodal distribution of binding energy with a maximum at -7.2 kcal/mol; whereas AMA1 exhibits a bimodal distribution with minimum at -6.8 and − 8.3 kcal/mol; suggesting various mechanisms of binding. Specifically; platencin was among the most potent dual-inhibitors with binding energies of -7.30 kcal/mol to PfGST and − 8.20 kcal/mol to AMA1. Pharmacophoric characteristics were found to be the hydrogen-bond acceptors; hydrophobic centers; and aromatic rings as determinants of dual-target activity; the optimal dual-target inhibitory potential occurring with compounds of balanced physicochemical properties. High-resolution molecular interaction mapping validated that while the two targets identify overlapping classes of interactions with the metabolites; PfGST interaction is dominated by hydrophobic contacts and AMA1 exploits higher electrostatic complementarity and hydrogen-bonding networks. ADMET profiling also revealed favorable drug-likeness in dual-inhibitory compounds of intermediate molecular size (420–500 Da) and moderate lipophilicity (LogP 3–6). This study provides a structural basis for rationale design of antimalarial compounds from microalgal metabolites. Our findings confirm the conformational selection hypothesis; in which these compounds selectively bind to and stabilize protein conformations that inhibit parasite function; possibly circumventing known resistance mechanisms.
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- Orexinergic system dysfunction is the fundamental basis for several neurological illnesses like narcolepsy, insomnia, and drug dependency, yet none of the existing medications are subtype receptor specific. This study examines 124 chemicals from neem to determine if they can be utilised as specific orexinergic receptor modulators using advanced computational methods. The methodology includes detailed clustering, pharmacophoric interaction, pharmacokinetic, statistical, and clustering analyses. Molecular property profiling indicated the majority of the compounds exhibit excellent drug-like qualities (MW 350-450 Da, LogP 0-2), while principal component analysis captured 100% structural variability between two components (92.5% and 7.5%, respectively). Molecular docking simulations indicated selective binding to the 6V9S receptor (-11.3 to -4 kcal/mol) over 4S0V (-9.7 to -4 kcal/mol). Lead compounds Neem_PDB_10257 (Tirucallol) (-11.3 kcal/mol) and Neem_PDB_12072821 ([(5 R,7 R,8 R,9 R,10 R,13S,17 R) -17-(2-methoxy-5-oxo-4,4,8,10,13-pentamethyl-3-oxo-5,6,7,9,11,12,16,17-octahydrocyclopenta[a]phenanthren-7-yl] acetate) were particularly 6V9S selective (>2 kcal/mol difference), whereas Neem_PDB_10160319 ((4S,4aS,5S,10S,13S,14S,17-4,4,10,13,14-pentam -1, 2, 3, 5, 6, 7, 11, 12, 15, 17-decahydrocyclopenta[a]phenanthren-16-one) was most sensitive towards 4S0V. Two top-ranked compound families were discovered by hierarchical cluster analysis with a distance requirement of 35 units, and receptor-specific dendrograms revealed distinctive subcluster branching patterns (4S0V: 5.5 and 6.7 unit subclusters; 6V9S: 7.1 and 7.2 unit subclusters). Interaction pattern (heatmap analysis) identified major interaction hotspots, including TYR348, TRP120, PHE227, and HIS350. Neem_PDB_163184214 (Meliatetraolenone) specifically targeted ASN318 in 6V9S, while Neem_PDB_54580354 (7-Benzoylnimbocinol) favored interaction with GLN134 in 4S0V (>90 interactions). These findings dispute the "one-pharmacophore" theory for orexinergic modulators, showing that intentional functionalization of NEM templates can deliver subtype-selective treatments with maximal sleep-wake modulation and low off-target effects.
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