Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights.

BACKGROUND: Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities. OBJECTIVE: To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA. METHODS: The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties. RESULTS: Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1 ) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability. CONCLUSION: Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

Design, Synthesis, and Biological and in silico Evaluation of Novel Indazole-pyridine Hybrids for the Treatment of Breast Cancer.

INTRODUCTION: The prevalence of breast cancer presents a substantial global health concern, underscoring the ongoing need for the development of inventive therapeutic remedies. METHODS: In this investigation, an array of novel indazole-pyridine hybrids (5a-h) have been designed and synthesized to assess their potential as candidates for treating breast cancer. Subsequently, we have conducted biological evaluations to determine their cytotoxic effects on the human MCF-7 breast cancer cell line. Furthermore, in silico analysis was conducted to estimate the inhibition potential of the compounds against TrkA (Tropomyosin receptor kinase A), a specific molecular target associated with breast cancer, through molecular docking. In silico physicochemical and pharmacokinetic predictions were made to assess the compounds' drug-like properties. RESULTS: Compound 5a emerged as the most active compound among the others with GI50 < 10 µg/ml. Besides, compound 5a showed high binding energy (BE -10.7 kcal/mol) against TrkA and was stabilized within the TrkA binding pocket through hydrophobic, H-bonding, and van der Waals interactions. In silico physicochemical and pharmacokinetic prediction studies indicated that compound 5a obeyed both Lipinski's and Veber's rule and displayed a versatile pharmacokinetic profile, implying compound 5a to appear as a viable candidate and that it could be further refined to develop therapeutic agents for potentially treating breast cancer. CONCLUSION: This study offers a promising direction for the advancement of innovative breast cancer treatments, highlighting the effectiveness of indazole-pyridine hybrids as potential anticancer agents. Further optimization and preclinical development are necessary to advance these compounds to clinical trials.

Discovery of Tropomyosin Receptor Kinase Inhibitors as New Generation Anticancer Agents: A Review.

BACKGROUND: The tropomyosin receptor kinases (TRKs) are crucial for many cellular functions, such as growth, motility, differentiation, and metabolism. Abnormal TRK signalling contributes to a variety of human disorders, most evidently cancer. Comprehensive genomic studies have found numerous changes in the genes that code for TRKs like MET, HER2/ErbB2, and EGFR, among many others. Precision medicine resistance, relapse occurring because of the protein point mutations, and the existence of multiple molecular feedback loops are significant therapeutic hurdles to the long-term effectiveness of TRK inhibitors as general therapeutic agents for the treatment of cancer. OBJECTIVE: This review is carried out to highlight the role of tropomyosin receptor kinase in cancer and the function of TRK inhibitors in the intervention of cancer. METHODS: Literature research has been accomplished using Google Scholar and databases like ScienceDirect, WOS, PubMed, SciFinder, and Scopus. RESULTS: In this review, we provide an overview of the main molecular and functional properties of TRKs and their inhibitors. It also discusses how these advancements have affected the development and use of novel treatments for malignancies and other conditions caused by activated TRKs. Several therapeutic strategies, including the discovery and development of small-molecule TRK inhibitors belonging to various chemical classes and their activity, as well as selectivity towards the receptors, have been discussed in detail. CONCLUSION: This review will help the researchers gain a fundamental understanding of TRKs, how this protein family works, and the ways to create chemical moieties, such as TRK inhibitors, which can serve as tailored therapies for cancer.

Identification of natural lead molecules as potential Trypanosoma cruzi cruzipain inhibitors and decoding the interaction mechanism for the treatment of Chagas disease: a computational biology analysis.

Chagas disease has grown into a serious public health threat, with a high morbidity rate, major social impact, and global neglect. Therapeutic adhesion, unwanted side-effects, and resistance make its present therapy ineffective. Discovery of more effective drugs is hence needed. Using natural compounds conjointly with computational methods helps better to find promising compounds, speeding up drug discovery process and reducing its cost. In the present study, a docking protocol against cruzipain (PDB: 3l06), an important druggable target, was applied to a library of 50 sorted natural compounds. Compounds were further analysed for binding mode and interactions with cruzipain active site, conformational alignment studies and in-silico pharmacokinetic studies so as to predict their plausible anti-cruzipain mechanism. The results provided computational insights into the molecular interaction of naturals against T. cruzi cruzipain. Study also lead to identification of Hinokiflavone; BA = -10.2 kcal mol-1 as reasonably promising potential natural cruzipain inhibitor.

Current Trends and Future Prospects on the Therapeutic Potential of Cordia dichotoma G. Forst.-A Valuable Folk Medicine.

BACKGROUND: Cordia dichotoma G. Forst (Boraginaceae), usually recognized as Clammy/ Indian cherry, is a familiar Ayurvedic, Unani, and modern herbal medicine used for diverse unrelated ailments since antiquity. It is rich in phytochemical constituents, has nutritional significance, and possesses enormous pharmacological properties. OBJECTIVE: This review has been established to highlight the importance of C. dichotoma G. Forst by providing comprehensive knowledge of its phytochemical, ethnobotanical, pharmacological, and toxicological aspects with a perception to foster pharmaceutical research to exploit its maximum potential as a therapeutic agent. METHODS: Literature research has been accomplished using Google Scholar and databases like Science Direct, WOS, PubMed, SciFinder, Scopus with updates until June 2022. RESULTS: The work is an update on C. dichotoma G. and it reviewed and analyzed its phytochemical, ethnobotanical, pharmacological and toxicological knowledge from early human communities to contemporary medicinal and pharmaceutical applications with comprehensive examination of myriad plausible applications in the present-day scientific milieu. The species depicted the presence of diverse phytochemical profiles, possibly justifying its bioactive potential. CONCLUSION: This review will help lay grounds to facilitate state-of-art research intended to acquire additional information about the plant. The study offers opportunities to explore bio-guided isolation strategies for isolating and purifying phytochemical constituents that are biologically effective including pharmacological and pharmaceutical aspects to better understand its clinical relevance. Exploring pure isolated phytoconstituents for their mode of action including estimation of their bioavailability and pharmacokinetic parameters would be of considerable interest in assessing the attained pharmacological effect. Clinical studies are required to validate the suitability of its traditional usage.

Emerging chemical scaffolds with potential SHP2 phosphatase inhibitory capabilities - A comprehensive review.

The drug discovery panorama is cluttered with promising therapeutic targets that have been deserted because of inadequate authentication and screening failures. Molecular targets formerly tagged as "undruggable" are nowadays being more cautiously cross-examined, and whilst they stay intriguing, numerous targets are emerging more accessible. Protein tyrosine phosphatases (PTPs) excellently exemplifies a class of molecular targets that have transpired as druggable, with several small molecules and antibodies recently turned available for further development. In this respect, SHP2, a PTP, has emerged as one of the potential targets in the current pharmacological research, particularly for cancer, due to its critical role in various signalling pathways. Recently, few molecules with excellent potency have entered clinical trials, but none could reach the clinic. Consequently, search for novel, non-toxic, and specific SHP2 inhibitors are on purview. In this review, general aspects of SHP2 including its structure and mechanistic role in carcinogenesis have been presented. It also sheds light on the development of novel molecular architectures belonging to diverse chemical classes that have been proposed as SHP2-specific inhibitors along with their structure-activity relationships (SARs), stemming from chemical, mechanism-based and computer-aided studies reported since January 2015 to July 2020 (excluding patents), focusing on their potency and selectivity. The encyclopedic facts and discussions presented herein will hopefully facilitate researchers to design new ligands with better efficacy and selectivity against SHP2.

A perspective review on fatty acid amide hydrolase (FAAH) inhibitors as potential therapeutic agents.

Fatty acid amide hydrolase (FAAH) is an important enzyme creditworthy of hydrolyzing endocannabinoids and related-amidated signalling lipids, discovery of which has pioneered novel arena of pharmacological canvasses to unwrap its curative potency in various diseased circumstances. It presents contemporary basis for understanding molecules regulating and mediating inflammatory reactions, pain, anxiety, depression, and neurodegeneration. FAAH inhibitors form vital approach for discovery of therapeutic agents that are concerned with local elevation of endocannabinoids under certain stimuli, debarring adverse/unwanted secondary effects from global activation of cannabinoid receptors by exogenous cannabimimetics. During past decades, several molecules with excellent potency developed through tailor-made approaches entered into clinical trials, but none could reach market. Hence, hunt for novel, non-toxic and selective FAAH inhibitors are on horizon. This review summarizes present perception on FAAH in conjunction with its structure, mechanism of catalysis and biological functions. It also foregrounds recent development of molecules belonging to diverse chemical classes as potential FAAH inhibitors bobbing up from in-depth chemical, mechanistic and computational studies published since 2015-November 2019, focusing on their potency. This review will assist readers to obtain rationale on FAAH as potential target for addressing various disease conditions, acquiring significant knowledge on recently established inhibitor scaffolds and their development potentials. New technologies including MD-MM simulations and 3D-QSAR studies allow mechanistic characterization of enzyme. Assessment of in-vitro and in-vivo efficacy of existing FAAH inhibitors will facilitate researchers to design novel ligands utilizing modern drug design methods. The discussions will also impose precaution in decision making process, quashing possibility of late stage failure.

Monoamine oxidase-B inhibitors as potential neurotherapeutic agents: An overview and update.

Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO-A/MAO-B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO-B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO-B inhibitors (MAO-BIs) belonging to diverse chemical scaffolds, arising from intensive chemical-mechanistic and computational studies documented during past 3 years (2015-2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO-BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO-BIs with superior activity profiles and critical discussions will inflict more caution in the decision-making process in the MAOIs discovery.

Scaffold hopping-guided design of some isatin based rigid analogs as fatty acid amide hydrolase inhibitors: Synthesis and evaluation.

Fatty acid amide hydrolase (FAAH) represents a potential therapeutic target for number of peripheral and nervous system related disorders including neuropathic pain and neuroinflammation. A library of N-(2,4-dichlorobenzoyl) isatin Schiff bases 7a-7l and 8a-8c were designed using the contemporary scaffold-hopping approach, synthesized and investigated for their ability to inhibit human FAAH enzyme using fluorescence based Cayman assay kit. The synthesized compounds inhibited FAAH with IC50 values in the range from 1.49 to 12,858 µM. Compound, 3-(1H-benzoimidazol-2-ylimino)-1-(2,4-dichlorobenzoyl)indolin-2-one (8c) showed strong inhibition against FAAH with IC50 of 1.49 ± 0.03 µM. SAR studies revealed various structural aspects important for the potency of these analogs. In particular, our findings suggested the requirement of hydrophobic aryl/heteroaryl moiety at C-3 position of isatin for optimum rigidity and steric hindrance to the scaffold. Additionally, molecular docking studies supported the experimental results revealing that compound 8c well-occupied the enzymatic cleft with optimal binding orientation and interactions within the active site of FAAH which resulted in reduced susceptibility of compound to nucleophilic attack and prevented it from leaving the active site, thereby increasing the inhibition. Also, compound 8c presented potent antidepressant and anxiolytic properties without any neurotoxicity. In silico molecular properties and ADMET descriptors calculations related the lead FAAH inhibitor 8c presented the satisfactory drug-like characteristics and ADMET properties and thus considered for further optimization. To the best of our knowledge this is the first report on the FAAH inhibitory properties of isatin-based analogs, revealing that both indoline skeleton and heteroaryl substitution at C-3 can modulate the activity of FAAH enzyme. In conclusion, the present study provided a better understanding of the molecular fragments requisite for maintaining and/or improving FAAH inhibition activity.