High-throughput computational screening for identification of potential hits against bacterial Acriflavine resistance protein B (AcrB) efflux pump.

Antibiotic resistance is a pressing global health challenge, driven in part by the remarkable efflux capabilities of efflux pump in AcrB (Acriflavine Resistance Protein B) protein in Gram-negative bacteria. In this study, a multi-approached computational screening strategy encompassing molecular docking, In silico absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis, druglikeness assessment, molecular dynamics simulations and density functional theory studies was employed to identify novel hits capable of acting against AcrB-mediated antibiotic resistance. Ligand library was acquired from the COCONUT database. Performed computational analyses unveiled four promising hit molecules (CNP0298667, CNP0399927, CNP0321542 and CNP0269513). Notably, CNP0298667 exhibited the highest negative binding affinity of -11.5 kcal/mol, indicating a possibility of strong potential to disrupt AcrB function. Importantly, all four hits met stringent druglikeness criteria and demonstrated favorable in silico ADMET profiles, underscoring their potential for further development. MD simulations over 100 ns revealed that the CNP0321542-4DX5 and CNP0269513-4DX5 complexes formed robust and stable interactions with the AcrB efflux pump. The identified hits represent a promising starting point for the design and optimization of novel therapeutics aimed at combating AcrB-mediated antibiotic resistance in Gram-negative bacteria.Communicated by Ramaswamy H. Sarma.

Exploration of limonoids for their broad spectrum antiviral potential via DFT, molecular docking and molecular dynamics simulation approach.

Limonoids serve as vital secondary metabolites. Citrus limonoids show a wide range of pharmacological potential. As a result of which limonoids from citrus are of considerable research interest. Identification of new therapeutic molecules from natural origins has been widely adopted as a successful strategy in drug discovery. This work mainly focused on the high-throughput computational exploration of the antiviral potential of three vital limonoids, i.e. Obacunone, Limonin and Nomilin against spike proteins of SARS CoV-2 (PDB:6LZG), Zika virus NS3 helicase (PDB:5JMT), Serotype 2 RNA dependent RNA polymerase of dengue virus (PDB:5K5M). Herein we report the molecular docking, MD simulation studies of nine docked complexes, and density functional theory (DFT) of selected limonoids. The results of this study indicated that all three limonoids have good molecular features but out of these three obacunone exerted satisfactory results for DFT, docking and MD simulation study.

Exploring biogenic chalcones as DprE1 inhibitors for antitubercular activity via in silico approach.

Cases of drug-resistant tuberculosis (TB) have increased worldwide in the last few years, and it is a major threat to global TB control strategies and the human population. Mycobacterium tuberculosis is a common causative agent responsible for increasing cases of TB and as reported by WHO, approximately, 1.5 million death occurred from TB in 2020. Identification of new therapies against drug-resistant TB is an urgent need to be considered primarily. The current investigation aims to find the potential biogenic chalcone against the potential targets of drug-resistant TB via in silico approach. The ligand library of biogenic chalcones was screened against DprE1. Results of molecular docking and in silico ADMET prediction revealed that ZINC000005158606 has lead-like properties against the targeted protein. Pharmacophore modeling was done to identify the pharmacophoric features and their geometric distance present in ZINC000005158606. The binding stability study performed using molecular dynamics (MD) simulation of the DprE1-ZINC000005158606 complex revealed the conformational stability of the complex system over 100 ns with minimum deviation. Further, the in silico anti-TB sensitivity of ZINC000005158606 was found to be higher as compared to the standards against Mycobacterium tuberculosis. The overall in silico investigation indicated the potential of identified hit to act as a lead molecule against Mycobacterium tuberculosis.

Multi-Targeted Design and Development of Dihydroisoquinolines as Potent Antimalarials.

BACKGROUND: Malaria is a serious parasitic infection with greater morbidity and motility in recent decades. Cysteine protease and DHODH enzyme serve as a potential target for antimalarial agents which inhibit parasite multiplication in the erythrocyte stage. Development of new leads which specifically target cysteine protease and DHODH enzyme can reduce the side effects and overcome multidrug resistance. OBJECTIVES: Representing the design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure-based drug design. METHODS: In present work, the rational development of antimalarial agents by targeting cysteine protease and DHODH has been made by integrating binding confirmation from virtual analysis and synthetic procedures. RESULTS: A novel series of dihydroisoquinolines was designed by structure-based drug design. Compounds from the dataset were screened for interaction at the target site by performing molecular docking study and subsequently, all molecules were screened for drug-like properties and toxicity, prior to synthesis molecules subjected to virtual filters. Designed molecules which exceed these virtual filters were synthesized, characterized and finally screened for antimalarial activity. CONCLUSION: In this work, it has been observed that compound A1, A5, A6 and A9 showed desirable biological activity towards targets and also specific hydrogen bonding interaction with the targets. Further optimization in leads yields a drug-like candidate and may overcome multidrug resistance.

Development of 'S', 'N' Heterocycles as Antimycobacterials Targeting Fatty Acid Biosynthesis.

BACKGROUND: Mycobacterium tuberculosis is a causative organism of tuberculosis, which is the most deadly disease after cancer in the current decade. The development of multidrug and broadly drug- resistant strains makes the tuberculosis problem more and more critical. In the last 40 years, only one molecule is added to the treatment regimen. Generally, drug design and development programs are targeted proteins whose function is known to be essential to the bacterial cell. OBJECTIVES: Here are the development of 'S', 'N' heterocycles as antimycobacterials targeting fatty acid biosynthesis are reported. MATERIALS AND METHODS: In the present communication, rational development of anti-mycobacterial agent's targeting fatty acid biosynthesis has been done by integrating the pocket modeling and virtual analysis. RESULTS: The identified potential 33 lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like IR, NMR spectroscopy and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds have shown profound antimycobacterial activity. CONCLUSION: In this present communication, we found that 3c, 3f, 3l and 4k molecules had expressive desirable biological activity and specific interactions with fatty acids. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates having fewer side effects.