In this study, we have employedin silicomethodology combining double pharmacophore based screening, molecular docking, and ADME/T filtering to identify dual binding site acetylcholinesterase inhibitors that can preferentially inhibit acetylcholinesterase and simultaneously inhibit the butyrylcholinesterase also but in the lesser extent than acetylcholinesterase. 3D-pharmacophore models of AChE and BuChE enzyme inhibitors have been developed from xanthostigmine derivatives through HypoGen and validated using test set, Fischer’s randomization technique. The best acetylcholinesterase and butyrylcholinesterase inhibitors pharmacophore hypotheses Hypo1_A and Hypo1_B, with high correlation coefficient of 0.96 and 0.94, respectively, were used as 3D query for screening the Zinc database. The screened hits were then subjected to the ADME/T and molecular docking study to prioritise the compounds. Finally, 18 compounds were identified as potential leads against AChE enzyme, showing good predicted activities and promising ADME/T properties.

A novel transacetylase (TAase) function of glutamine synthetase (GS) in bacterial species such asMycobacterium smegmatisandMycobacterium tuberculosisH37Rv was established by us, termed as mycobacterial TAase (MTAase). Several polyphenolic acetates (PAs) were found to be substrates for MTAase by inhibiting certain receptor proteins such as glutathione S-transferase by way of acetylation. The present work describes the descriptor-based 2D-QSAR studies developed for a series of PA synthesized by us and evaluated for MTAase and antimycobacterial activity using stepwise multiple linear regression method with the kinetic constants and the minimum inhibitory constant (MIC) as the dependent variables, to address the fact that TAase activity was leading to the antimycobacterial activity. Further, blind docking methods using AutoDock were carried out to study the interaction of potent PA with the crystal structure ofM. tuberculosisGS. PAs were predicted to bindM. tuberculosisGS on the protein surface away from the known active site of GS. Subsequent focussed/refined docking of potent PA with GS showed that theε-amino group of Lys4 of GS formed a cation-πinteraction with the benzene ring of PA. Also, ADMET-related descriptors were calculated to predict the pharmacokinetic properties for the selection of the effective and bioavailable compounds.

Niacinamide, a derivative of vitamin B3, has been shown to reduce skin pigmentation (i.e., acting as a brightening agent) and inflammatory responses such as dermatitis and acne vulgaris. However, niacinamide is a hydrophilic compound and poor partitioning to the lipid matrix in the uppermost layer of the skin (the stratum corneum or SC) limits its delivery to the skin. This necessitates the use of penetration enhancers to increase its bio-availability. In this study, we used computer simulations to investigate the skin penetration of niacinamide alone and in combination with other brightening agents that are also shown to be skin penetration enhancers, namely undecylenoyl phenylalanine (Sepiwhite^®), bisabolol, or sucrose dilaurate. Molecular dynamics simulations were performed to reveal molecular interactions of these brightening agents with a lipid bilayer model that mimics the SC lipid matrix. We observed minimal penetration of niacinamide into the SC lipid bilayer when applied alone or in combination with any one of the three compounds. However, when all three compounds were combined, a notable increase in penetration was observed. We showed a 32% increase in the niacinamide diffusivity in the presence of three other brightening agents, which also work as penetration enhancers for niacinamide. These findings suggest that formulations containing multiple brightening agents, which work as penetration enhancers, may improve skin penetration of niacinamide and enhance the effectiveness of the treatment.

The stratum corneum (SC) forms the outermost layer of the skin, playing a critical role in preventing water loss and protecting against external biological and chemical threats. Approximately 90% of the SC consists of large, flat corneocytes, yet its barrier function primarily relies on the intercellular lipid matrix that surrounds these cells. Traditional methods for characterizing these lipids, such as Fourier transform infrared spectroscopy (FTIR), typically involve macroscopic analysis using attenuated total reflection (ATR) techniques. In this study, we introduce a novel approach for investigating SC samples at a microscopic level to gain detailed chemical insights and assess sample heterogeneity. Special emphasis is placed on advanced hyperspectral data pre-processing to ensure the accuracy and reliability of the results. We also evaluate methods for filtering out spectral data that significantly deviate from the mean and analyze the extracted mean spectra, the intensities of specific infrared peaks, and their ratios. The novelty of this work lies in its microscopic approach to analyzing the SC lipid matrix, diverging from the traditional macroscopic FTIR–ATR methods. By focusing on hyperspectral imaging and developing robust pre-processing techniques, this study provides more localized, high-resolution chemical insights. This microscopic perspective opens up the possibility of detecting subtle heterogeneities within the skin’s lipid matrix, offering deeper, previously unattainable understanding of the SC’s barrier function. Additionally, the exploration of spectral filtering methods enhances the precision of the analysis, paving the way for more refined and reliable investigations of skin structure and behavior in future research.

Caffeoyl hexapeptide-9 (CH-9) is a novel cosmetic peptide designed by conjugating hexapeptide-9 (H-9), a known collagen-mimetic peptide with established skin anti-aging activity, with caffeic acid (CA) via an amide bond, leveraging peptide-drug conjugate (PDC) design principles. In ultraviolet (UV)-irradiated cellular and skin models, CH-9 outperformed H-9 in preserving cell viability, restoring collagen types I, III, and IV, and suppressing interleukin-6 and -8 secretion. Additionally, its direct antioxidant activity, absent in H-9, was demonstrated in vitro by scavenging of hydroxyl and peroxyl radicals. Molecular docking indicated CH-9 interacted with the catalytic domain of matrix metalloproteinase 2 (MMP2), a key enzyme in collagen degradation during photoaging, suggesting a potential inhibition of its activity. Molecular dynamics (MD) simulations revealed an improved insertion of CH-9 into a stratum corneum (SC) lipid bilayer compared to H-9, consistent with enhanced skin permeation in vivo. Moreover, CH-9 exhibited improved aqueous and cosmetic serum stability over CA. In a 28-day clinical study, topical application of CH-9 significantly improved skin elasticity and firmness compared to H-9. This work demonstrates that the PDC-based conjugate CH-9 combines enhanced anti-photoaging efficacy with improved transdermal permeation and stability, highlighting a promising strategy for the development of advanced cosmetic ingredients.