Applications of molecular docking in natural products-based drug discovery

Natural products have a long history of use in the treatment of various diseases particularly in developing countries. The use of compounds of natural origin as lead compounds for the development of conventional drugs is widely recognised. Natural product-based drug discovery efforts in developing countries mostly involve the use of crude extracts in in-vitro and/or in-vivo assays. There are limited efforts at isolating active principles for structure elucidation studies. Studies that isolate pure secondary metabolites and characterize their structures have limited bioactivity evaluations. In conventional drug discovery programs, molecular docking serves as a useful tool for predicting interactions of small molecules with drug target(s) to guide synthesis decisions. Medicinal chemists use this tool to predict and synthesize compounds likely to have pharmacological activity and thus save time and cost for drug discovery. Efforts have been made to incorporate molecular docking techniques into natural products-based drug discovery. The objective of this review is to discuss molecular docking in natural product drug discovery programs with the goal of providing easy-to-understand information to help beginners interested in incorporating molecular docking in their research. This is expected to enhance natural product screening programs by predicting which phytochemicals are likely to show success, especially in new disease situations such as COVID-19. Applications in the repositioning of plants for emerging conditions are also discussed. © 2023

Spike Protein Potential Receptors Study: Comparative Computational Analysis Approach on SARS-CoV-2-AC2/CD147 Complexes

SARS-CoV-2 invades host cells via interaction of its spike protein with the human angiotensin-converting enzyme 2 as the receptor. CD147, as a biomarker for hyperinflammation, was found to be the functional receptor for SARS-CoV-2 and an additional cell entry route. In this paper, we focused our analysis on the initial step of virus infection by comparing the affinity, stability, and specificity of the SARS-CoV-2 spike 1-AC2 and SARS-CoV-2 spike 1-CD147 complexes. Protein-protein docking was utilized for identifying the hotspot residues in the interface of spike protein with AC2 and CD147. The results of binding free energies showed a high affinity of SP1-AC2 complex (-52.97 kcal/mol) compared with SP1-CoV2/CD147 (-35.75 kcal/mol). RMSF values indicate that the spike protein of SARS-CoV-2 RBD is more compatible with binding to the human ACE2 with high flexibility. Computational analysis of binding modes and protein contacts reported that CD147 and ACE2 might be two complementary receptors mediating virus infection and confirmed the experimental results previously. © 2022 by the authors.

Human Vitamin K Epoxide Reductase as a Target of Its Redox Protein.

Human vitamin K epoxide reductase (hVKORC1) enzymatic activity requires an initial activation by a specific redox protein, a less studied step in the hVKORC1 vital cycle. Significant steric conditions must be met by enzymes, being that to adapt their configurations is mandatory for hVKORC1 activation. We studied, by molecular dynamics (MD) simulations, the folding and conformational plasticity of hVKORC1 in its inactive (fully oxidised) state using available structures, crystallographic and from de novo modelling. According to the obtained results, hVKORC1 is a modular protein composed of the stable transmembrane domain (TMD) and intrinsically disordered luminal (L) loop, possessing the great plasticity/adaptability required to perform various steps of the activation process. The docking (HADDOCK) of Protein Disulfide Isomerase (PDI) onto different hVKORC1 conformations clearly indicated that the most interpretable solutions were found on the target closed L-loop form, a prevalent conformation of hVKORC1's oxidised state. We also suggest that the cleaved L-loop is an appropriate entity to study hVKORC1 recognition/activation by its redox protein. Additionally, the application of hVKORC1 (membrane protein) in aqueous solution is likely to prove to be very useful in practice in either in silico studies or in vitro experiments.

Bioinformatics analysis of SARS-CoV-2 protein targets.

COVID-19 epidemic is still raging around the world, and there is no effective specific treatment against the virus. In this paper, the SARS-CoV-2 viral and host cellular protein targets, which were provided by Chemical s Service (CAS), were analyzed through bioinformatics methods. GO enrichment and protein-protein network analysis methods were applied to explore biofunctions of these protein targets. Results showed that human clathrin-mediated endocytosis and dependent endocytosis were vital pathways for viruses entering host cells. In addition, viral ORF6 protein could influence the process that Nuclear Localization Signal (NLS) mediates the protein transferring into nucleus. These results may provide potential for the antiviral therapies and vaccines against SARS-CoV-2. (English) [ FROM AUTHOR] 目前新型冠状病毒肺炎(COVID-19)疫情仍在全球肆虐,但尚无针对该病毒的治疗特效药。在此背景,以美国化学文摘社(Chemical s Service, CAS)提供的SARS-CoV-2病毒及宿主蛋白靶标为研究对象,运用基因功能富集、蛋白网络等方法进行生物信息分析。结果发现,人网格蛋白介导型内吞和依赖型内吞是病毒进入宿主细胞的重要途径；病毒ORF6(Open Reading Frame,ORF)蛋白可影响细胞内核定位信号(Nuclear Localization Signal,NLS)介导蛋白入核的生物学过程。这些研究结果可为抗新型冠状病毒药物和疫苗的研发提供更多的可能性和思路. (Chinese) [ FROM AUTHOR] Copyright of Chinese Journal of Bioinformatics is the property of Bioinformatics and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Potential Protein and Enzyme Targets for In-silico Development and Repurposing of Drug Against Coronaviruses

Drug development is a tedious, expensive and time consuming process that is accompanied with huge amount of uncertainty due to very low success rate using conventional methods. However, in-silico techniques have helped society in drug designing and repurposing at minimal cost by shortlisting potentially hit compounds from huge libraries in a short span of time. This computational methodology has made a prominent contribution in the virtual screening of therapeutically relevant drugs for various viral diseases. It has helped in providing relevant information regarding drug-target interaction and mechanism through which we can modify our drug compound for better efficiency. In-silico tools additionally helps in predicting toxicity and pharmacokinetics, which can further help in clearing trials and approval. The recent outbreak of novel coronavirus (COVID-19) has resulted in a huge number of deaths and affected the economy of the world adversely. Computational methods have played a major role in shortlisting compounds that can inhibit viral infection by targeting various components of this virus which are essential in spreading the infection and replication mechanism. The repurposing of the drug against coronavirus has become a lot easier and efficient with the advancement in these computational techniques. Hence, this review covers the recent developments in the virtual screening of potentially hit compounds against COVID-19.

SARS-CoV-2 protein drug targets landscape: a potential pharmacological insight view for the new drug development.

Introduction: Protein drug targets play a significant choice in different stages of the drug discovery process. There is an urgent need to understand the drug discovery approaches and protein drug targets (PDT) of SARS-CoV-2, with structural insights for the development of SARS-CoV-2 drugs through targeted therapeutic approach.Areas covered: We have described the protein as a drug target class and also discussed various drug discovery approaches for SARS-CoV-2 involving the protein drug targets such as drug repurposing study, designing of viral entry inhibitors, viral replication inhibitors, and different enzymes of the virus. We have performed comprehensive literature search from the popular databases such as PubMed Google scholar, Web of Science, and Scopus. Finally, we have illustrated the structural landscape of different significant viral proteins (3 CLpro or Mpro, PLpro, RdRp, helicase, S protein) and host proteins as drug targets (cathepsin L, furin, TMPRSS2, ACE2).Expert opinion: The structural landscape of PDT with their binding pockets, and significant residues involved in binding has been discussed further to better understand the PDT and the structure-based drug discovery for SARS-CoV-2. This attempt will increase more therapeutic options, and combination therapies with a multi-target strategy.

Nutrition of the COVID-19 patient in the intensive care unit (ICU): a practical guidance.

Five to 10% of the coronavirus SARS-CoV-2-infected patients, i.e., with new coronavirus disease 2019 (COVID-19), are presenting with an acute respiratory distress syndrome (ARDS) requiring urgent respiratory and hemodynamic support in the intensive care unit (ICU). However, nutrition is an important element of care. The nutritional assessment and the early nutritional care management of COVID-19 patients must be integrated into the overall therapeutic strategy. The international recommendations on nutrition in the ICU should be followed. Some specific issues about the nutrition of the COVID-19 patients in the ICU should be emphasized. We propose a flow chart and ten key issues for optimizing the nutrition management of COVID-19 patients in the ICU.