Due to the unavailability specific drugs or vaccines (FDA approved) that can cure COVID-19, the development of potent antiviral drug candidates/therapeutic molecules against COVID-19 is urgently required. This study was aimed at in silico screening and study of polyphenolic phytochemical compounds in a rational way by virtual screening, molecular docking and molecular dynamics studies against SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) enzymes. The objective of the study was to identify plant-derived polyphenolic compounds and/or flavonoid molecules as possible antiviral agents with protease inhibitory potential against SARS-CoV-2. In this study, we report plant-derived polyphenolic compounds (including flavonoids) as novel protease inhibitors against SARS-CoV-2. From virtual docking and molecular docking study, 31 polyphenolic compounds were identified as active antiviral molecules possessing well-defined binding affinity with acceptable ADMET, toxicity and lead-like or drug-like properties. Six polyphenolic compounds, namely, enterodiol, taxifolin, eriodictyol, leucopelargonidin, morin and myricetin were found to exhibit remarkable binding affinities against the proteases with taxifolin and morin exhibiting the highest binding affinity toward Mpro and PLpro respectively. Molecular dynamics simulation studies of these compounds in complex with the proteases showed that the binding of the compounds is characterized by structural perturbations of the proteases suggesting their antiviral activities. These compounds can therefore be investigated further by in vivo and in vitro techniques to assess their potential efficacy against SARS-CoV-2 and thus serve as the starting point for the development of potent antiviral agents against the deadly COVID-19. Communicated by Ramaswamy H. Sarma

The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent targeting, the oncoprotein is being expunged from the ‘undruggable’ list of proteins. This feat has seen some covalent drugs at different stages of clinical trials. The advancement of AMG510 and MRTX849 as inhibitors of cysteine mutated KRAS (KRAS^G12C) to phase-III clinical trials informed the biased selection of AMG510 and MRTX849 for this study. Despite this advance, the molecular and atomistic modus operandi of these drugs is yet to come to light. In this study, we employed computational tools to unravel the atomistic interactions and subsequent conformational effects of AMG510 and MRTX849 on the mutant KRAS^G12C. It was revealed that AMG510 and MRTX849 complexes presented similar total free binding energies, (ΔG_bind), of –88.15 ± 5.96 kcal/mol and –88.71 ± 7.70 kcal/mol, respectively. Gly10, Lys16, Thr58, Gly60, Glu62, Glu63, Arg68, Asp69, Met72, His95, Tyr96, Gln99, Arg102 and Val103 interacted prominently with AMG510 and MRTX849. These residues interacted with the pharmacophoric moieties of AMG510 and MRTX849 via hydrogen bonds with decreasing bond lengths at various stages of the simulation. These interactions together with pi-pi stacking, pi-sigma and pi-alkyl interactions induced unfolding of switch I whiles compacting switch II, which could interrupt the binding of effector proteins to these interfaces. These insights present useful atomistic perspectives into the success of AMG510 and MRTX849 which could guide the design of more selective and potent KRAS inhibitors. Communicated by Ramaswamy H. Sarma

Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%–5% of non-small cell lung cancers (NSCLCs). NSCLC is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Available treatment options for ALK-positive NSCLCs involve the use of ALK tyrosine kinase inhibitors (ALK-TKIs) which have shown to be effective with a high response rate. Nonetheless, the emergence of multiple compound mutations such as I1171N + F1174I or I1171N + L1198H has been reported to cause resistance to all approved ALK-TKIs. However, the underlying molecular mechanisms surrounding the impact of these compound mutants remain poorly understood. Hence, we performed molecular dynamics simulations to characterize the structural effects and functional implications of these compound mutations. Findings revealed a destabilizing effect on ALK by mutants as compared to the wild-type ALK structure. Also, further insights revealed a lower root-mean-squared fluctuation, radius of gyration, and solvent-accessible surface area values of I1171N + F1174I and I1171N + L1198H ALK compound mutations suggesting that the mutants have a more compact structure and a smaller surface area than the wild-type protein. The mutants also distorted the activation loop residues (Tyr1278, Tyr1282, and Tyr1283) in the ALK structure, which further identify them as possible disruptors of phosphorylation. In contrast to wild conformation, the mutant conformations exhibited a reduced node degree in their residue interaction networks. Collectively, our findings provide deeper insights into the deleterious effects of I1171N + F1174I and I1171N + L1198H ALK compound mutations, which may contribute to NSCLC pathogenesis. Communicated by Ramaswamy H. Sarma

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC₅₀ = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood–brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs. Graphical Abstract

The therapeutic potential of psilocybin in treating psychiatric disorders has gained attention recently. While most research has focused on isolated psilocybin, evidence suggests that whole mushroom extracts exhibit greater efficacy, implicating a possible entourage effect of additional bioactive compounds. This study aimed to elucidate the holistic neuropharmacological effects of psilocybin-producing mushroom compounds through a computational framework incorporating network pharmacology, molecular docking, and molecular dynamics. Fifteen mushroom-derived compounds were identified from literature, of which eight exhibited favorable pharmacokinetic profiles. Target prediction and network analysis identified 44 brain-localized proteins with partial biological connectivity. Functional enrichment and pathway analyses implicate key neurological pathways. The compounds exhibited strong docking scores to neurologically relevant targets. Several compounds formed stable salt bridges with the Asp155 residue of HTR2A, mirroring serotonin’s binding behavior. Molecular dynamics simulations further confirmed high residence stability of the compounds within the binding pockets of HTR2A and MAOA. These findings support a mechanistic rationale for the enhanced efficacy of whole mushroom extracts over isolated psilocybin and underscore the therapeutic potential of other constituent compounds. The study highlights the importance of multi-target interactions in mediating neuropsychiatric effects and provides a foundation for further investigations into the synergistic roles of these compounds in CNS modulation.