Journal of Molecular Docking

Identification of Bioactive Molecules from Combretum micranthum as Potential Inhibitors of α-amylase through Computational Investigations

Damilola Samuel Bodun — 2022-12-31

The rising prevalence of diabetes necessitates continued research into natural antidiabetic medicines that target a key biochemical enzyme involved. The α-amylase enzyme is involved in the digestion of starch, glycogen, and disaccharides in the gastrointestinal tract. Its essential roles and distinct properties make it an effective antidiabetic target. This work aimed to use in silico approaches to find possible α-amylase inhibitors from Combretum micranthum bioactive substances. On the Schrödinger Maestro 12.5, over 50 C. micranthum compounds were screened, followed by MM-GBSA and ADMET (absorption, distribution, metabolism, excretion, and toxicity) studies of the highest affinity compounds. The α-amylase binding affinities were higher for rutin trihydrate and myricetin-3-rutinoside (-12.162 kcal/mol and -10.935 kcal/mol, respectively). They reacted with amino acids that are required for the inhibition of α-amylase. As a result, these compounds have the structural characteristics, binding affinities, and molecular interactions necessary as α-amylase inhibitors and could be turned into antidiabetic medicines through lead optimization and experimental research.

Alantolactone: A Potential Multitarget Drug candidate for Prevention of SARS-CoV-2 Cell Entry

Erum Zafar — 2022-12-31

The novel strain of coronavirus, SARS-CoV-2, has spread adverse effects on human health with high mortality rates worldwide. SARS-CoV-2 is a severe respiratory disease expressed through positive single stranded RNA enveloped virus. SARS-CoV-2 had affected globally and is influencing the economy as well. The rapidly spreading coronavirus infection has discombobulated the researchers in perpetuate search for different or effective therapeutic drugs. Most of the connatural products are proposed to have significant clinical outcomes but their pathways of action are not clear. This molecular docking study presents alantolactone, a bio-active member of sesquiterpene family as a successful inhibitor of SARS-Cov-2 and human receptor proteins. Alantolactone shows high binding affinity with the SARS-CoV-2 target proteins such as spike glycoprotein (S-protein), nucleocapsid protein (N-protein), main protease (M^Pro), and papain-like protease (PL^Pro) with a binding affinity of -7.3 kcal/mol, -7.9 kcal/mol, -6.8 kcal/mol, and -7.1 kcal/mol, respectively as well as human receptor proteins associated with the recognition, binding and biogenesis of SARS-CoV-2 such as angiotensin-converting enzyme 2 (ACE-2), receptor binding domain (S1-RBD) and ACE2 interphase, furin, adaptor-associated protein kinase 1 (AAK1), cyclin G-associated kinase (GAK), and both closed and open configurations of the two-pore channel (TPC2) with binding energies of -6.7 kcal/mol, - 6.9 kcal/mol, -8.1 kcal/mol, -7.3 kcal/mol, and -7.9 kcal/mol, respectively. Molecular docking and ADMET properties and toxicity predictions suggest that alantolactone could effectively binds with various viral target protein and human target proteins and could be developed into a novel SARS-coV-2 inhibitor.

Docking and Dynamics Study of Phytochemicals as Potent Inhibitors against SARS-CoV-2 Main Protease

Palla Ramprasad — 2022-12-31

Coronavirus Infectious Disease-19 (COVID-19) caused by coronavirus 2 is a global health hazard. The lack of medications against the disease is a major concern of the research community today. Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease (SARS-CoV-2 M^Pro) is the most extensively studied protein responsible for spreading disease. Several plant-based products are utilized to treat the disease's symptoms. Here, we have attempted to screen 377 phytocompounds against the target computationally. We have sorted eight best-pose compounds based on docking studies for further analysis. Lipinski and Adsorption, Distribution, Metabolism, Elimination/Toxicity (ADME/T) properties were also evaluated to assess the drug-like properties and toxicity of the screened compounds. Finally, we discovered Coruscanone to be the most effective lead compound for the target. The best complex was further undertaken for dynamic simulation. RMSD, RMSF, h-bond, and Rg were analyzed and studied related to the reference compound. The study additionally continues to elucidate its inhibitory action via in vitro studies.

De Novo Class of Momordicoside with Potent and Selective Tumor Cell Growth Inhibitory Activity as Pyruvate Kinase Muscle Isozyme 2 and Anti-apoptotic Myeloid Leukemia 1 Inhibitors

Tope Abraham Ibisanmi — 2022-12-31

The difficulty in treating cancer resides in targeting abnormal proliferation while protecting normal proliferation, necessitating a thorough comprehension of the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is the hallmark of many cancers, the aim of which this research is ready to evaluate. Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Docking scores of ligands used against PKM2 range from –9.36 to –12.1 kcal/mol, wherein momordicoside-F2 had the highest score (2.1 kcal/mol), performing better than the FDA-approved drug benserazide. Likewise, the scores ranged between –8.51 and –12.05 kcal/mol for Anti-apoptotic Myeloid Leukemia 1 (MCL-1), with momordicoside-F1 being the highest-ranked compound. The RMSD plots depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations were also observed, indicating their increased interaction potential, implying that the ligands could adapt well in the protein's binding pocket. The SASA analysis results show that the ligands retained inside their shallow binding pocket. The phylogenetic tree obtained implies the likelihood of recurring results of the in silico profiling. Conclusively, this research unveils that Mormordicoside F1 shows good stability with MCL-1, likewise, momordicoside-F2 against PKM2. These hits can be a better re-purposing option.

Phytochemical Molecules Binding with the Proteins of Mycolic Acid Synthesis Pathway of Mycobacterium tuberculosis

Rishabh Gaur — 2022-12-31

Resistance against anti-tubercular drugs is a significant problem. This elucidates the need for novel drug targets. Altering and targeting the enzymes involved in cell wall synthesis led to fatal damage to the bacterial cell. Mycolic acids are critically responsible for the virulence of Mycobacterium Tuberculosis. This pathway represents an essential reservoir of novel targets for developing new TB drugs. The study aims to identify phytochemicals with the capacity to bind with enzymes of mycolic acid synthesis pathways. This study shows the interaction between phytochemicals and proteins responsible for mycolic acid synthesis is shown through bioinformatics & molecular docking tools. Docking showed binding affinity between protein molecules of the mycolic acid synthesis pathway and ligand molecules in the study. PKS13 (polyketide synthase) interacts with the ligand beta-amyrin acetate with a vina score of -7.1 Kcal/mol. At the same time, its binding energy with Piperine is -6.8 Kcal/mol. DprE1 (Decaprenylphosphoryl-bet-D-ribose-2-epimerase), the other protein docked with beta-amyrin acetate, showed a vina score of -9.7 Kcal/mol binding energy. Piperine with DprE1 exhibits interaction with a score of -8.3 Kcal/mol. Beta-amyrin acetate is docked with a score of -6.9 Kcal/mol against KasA (Beta-ketoacyl-acyl carrier protein synthase). On the other hand, Piperine with KasA gave a result of -7.0 Kcal/mol. Piperine and Beta-amyrin acetate binds to PKS13, DprE1 & KasA protein/enzymes responsible for mycolic acid biosynthesis.