Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based ...drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.
Multiple drug-resistant bacteria are a severe and growing public health concern. Because relatively few antibiotics have been approved over recent years and because of the inability of existing ...antibiotics to combat bacterial infections fully, demand for unconventional biocides is intense. Metallic nanoparticles (NPs) offer a novel potential means of fighting bacteria. Although metallic NPs exert their effects through membrane protein damage, superoxide radicals and the generation of ions that interfere with the cell granules leading to the formation of condensed particles, their antimicrobial potential, and mechanisms of action are still debated. This article discusses the action of metallic NPs as antibacterial agents, their mechanism of action, and their effect on bacterial drug resistance. Based on encouraging data about the antibacterial effects of NP/antibiotic combinations, we propose that this concept be thoroughly researched to identify means of combating drug-resistant bacteria.
Cyclin-dependent kinase 2 (CDK2) is an essential protein kinase involved in the cell cycle regulation. The abnormal activity of CDK2 is associated with cancer progression and metastasis. Here, we ...have performed structure-based virtual screening of the PubChem database to identify potent CDK2 inhibitors. First, we retrieved all compounds from the PubChem database having at least 90% structural similarity with the known CDK2 inhibitors. The selected compounds were subjected to structure-based molecular docking studies to investigate their pattern of interaction and estimate their binding affinities with CDK2. Selected compounds were further filtered out based on their physicochemical and ADMET properties. Detailed interaction analysis revealed that selected compounds interact with the functionally important residues of the active site pocket of CDK2. All-atom molecular dynamics simulation was performed to evaluate conformational changes, stability and the interaction mechanism of CDK2 in-complex with the selected compound. We found that binding of 6-
,6-
-dimethyl-9-(2-phenylethyl)purine-2,6-diamine stabilizes the structure of CDK2 and causes minimal conformational change. Finally, we suggest that the compound (PubChem ID 101874157) would be a promising scaffold to be further exploited as a potential inhibitor of CDK2 for therapeutic management of cancer after required validation.
A novel severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) causing COVID-19 pandemic in humans, recently emerged and has exported in more than 200 countries as a result of rapid ...spread. In this study, we have made an attempt to investigate the SARS-CoV-2 genome reported from 13 different countries, identification of mutations in major coronavirus proteins of these different SARS-CoV-2 genomes and compared with SARS-CoV. These thirteen complete genome sequences of SARS-CoV-2 showed high identity (>99%) to each other, while they shared 82% identity with SARS-CoV. Here, we performed a very systematic mutational analysis of SARS-CoV-2 genomes from different geographical locations, which enabled us to identify numerous unique features of this viral genome. This includes several important country-specific unique mutations in the major proteins of SARS-CoV-2 namely, replicase polyprotein, spike glycoprotein, envelope protein and nucleocapsid protein. Indian strain showed mutation in spike glycoprotein at R408I and in replicase polyprotein at I671T, P2144S and A2798V,. While the spike protein of Spain & South Korea carried F797C and S221W mutation, respectively. Likewise, several important country specific mutations were analyzed. The effect of mutations of these major proteins were also investigated using various in silico approaches. Main protease (Mpro), the therapeutic target protein of SARS with maximum reported inhibitors, was thoroughly investigated and the effect of mutation on the binding affinity and structural dynamics of Mpro was studied. It was found that the R60C mutation in Mpro affects the protein dynamics, thereby, affecting the binding of inhibitor within its active site. The implications of mutation on structural characteristics were determined. The information provided in this manuscript holds great potential in further scientific research towards the design of potential vaccine candidates/small molecular inhibitor against COVID19.
Protein-protein interaction (PPI) is necessary for most of the biological processes and requisite for host-pathogen communication. Most of the threatening human diseases are caused by different types ...of interactions of proteins with their prior infected proteins or with pathogen's proteins. Understanding of involved mechanisms of interacting pairs, functional domains and characterizing specific molecular interaction of host and pathogen is critical. In this era of advanced research in medical and pharmaceutical sciences, the treatment of severe diseases is being tackled at genetic and PPI level. In this review, a brief introduction and application of PPI is described. Moreover, the classifications of PPI and their application in diseases are highlighted. Furthermore, methods for prediction of PPI are also discussed including brief introduction and update on detection techniques. We hope this review will prove to be very helpful for researchers to get better understanding and update on PPI.
Background: Neurodegenerative disorders (NDs) are diverse group of disorders characterized
by escalating loss of neurons (structural and functional). The development of potential
therapeutics for NDs ...presents an important challenge, as traditional treatments are inefficient and
usually are unable to stop or retard the process of neurodegeneration. Computer-Aided Drug Design
(CADD) has emerged as an efficient means of developing candidate drugs for the treatment of
many disease types. Applications of CADD approach to drug discovery are progressing day by day.
The recent tendency in drug design is to rationally design potent therapeutics with multi-targeting
effects, higher efficacies, and fewer side effects, especially in terms of toxicity.
Methods: A wide literature search was performed for writing this review. An updated view on different
types of NDs, their effect on human population and a brief introduction to CADD, various
approaches involved in this technique, ranging from structural-based to ligand-based drug design
has been discussed. The successful application of CADD approaches for the treatment of neurodegenerative
disorders is also included in this review.
Results: In this review, we have briefly described about CADD and its use in the development of
the therapeutic drug candidates against NDs. The successful applications, limitations and future
prospects of this approach have also been discussed.
Conclusion: CADD can assist researchers studying interactions between drugs and receptors. We
believe this review will be helpful for better understanding of CADD and its applications towards
the discovery of new drug candidates against various fatal NDs.
Interactions between myoblasts and the surrounding microenvironment led us to explore the role of fibromodulin (FMOD), an extracellular matrix protein, in the maintenance of myoblast stemness and ...function. Microarray analysis of FMODkd myoblasts and in silico studies were used to identify the top most differentially expressed genes in FMODkd, and helped establish that FMOD‐based regulations of integral membrane protein 2a and clusterin are essential components of the myogenic program. Studies in knockout, obese, and diabetic mouse models helped characterize the operation of a novel FMOD‐based regulatory circuit that controls myoblast switching from a myogenic to a lipid accumulation fate. FMOD regulation of myoblasts is an essential part of the myogenic program, and it offers opportunities for the development of therapeutics for the treatment of different muscle diseases.—Lee, E. J., Jan, A. T., Baig, M. H., Ahmad, K., Malik, A., Rabbani, G., Kim, T., Lee, I.‐K., Lee, Y. H., Park, S.‐Y., Choi, I. Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte‐like cells. FASEB J. 32, 768–781 (2018). www.fasebj.org
Cyclobenzaprine hydrochloride (CBH) is a well-known muscle relaxant that is widely used to relieve muscle spasms and other pain associated with acute musculoskeletal conditions. In this study, we ...elucidated the binding characteristics of this muscle relaxant to human serum albumin (HSA). From a pharmaceutical and biochemical viewpoint, insight into the structure, functions, dynamics, and features of HSA-CBH complex holds great importance. The binding of CBH with this major circulatory transport protein was studied using a combination of biophysical approaches such as UV-VIS absorption, fluorescence quenching, and circular dichroism (CD) spectroscopy. Various
techniques, molecular docking and molecular dynamics, were also used to gain deeper insight into the binding. A reduction in the fluorescence intensities of HSA-CBH complex with a constant increase in temperature, revealed the static mode of protein fluorescence quenching upon CBH addition, which confirmed the formation of the HSA-CBH ground state complex. The alteration in the UV-VIS and far-UV CD spectrum indicated changes in both secondary and tertiary structures of HSA upon binding of CBH, further proving CBH binding to HSA. The analysis of thermodynamic parameters ∆H° and ∆S° showed that binding of CBH to HSA was dominated by intermolecular hydrophobic forces. The results of the molecular docking and molecular dynamics simulation studies also confirmed the stability of the complex and supported the experimental results.
The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the ...occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.
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