Anti-COVID-19 terpenoid from marine sources: A docking, admet and molecular dynamics study.

Traditional medicines contain natural products (NPs) as main ingredient which always give new direction and paths to develop new advanced medicines. In the COVID-19 pandemic, NPs can be used or can help to find new compound against it. The SARS coronavirus-2 main protease (SARS CoV-2 Mpro) enzyme, arbitrate viral replication and transcription, is target here. The study show that, from the electronic features and binding affinity of all the NPs with the enzyme, the compounds with higher hydrophobicity and lower flexibility can be more favorable inhibitor. More than fifty NPs were screened for the target and one terpenoid (T3) from marine sponge Cacospongia mycofijiensis shows excellent SARS CoV-2 Mpro inhibitory activity in comparison with known peptide based inhibitors. The molecular dynamics simulation studies of the terpenoids with the protein indicates that the complex is stable and hydrogen bonds are involved during the complexation. Considering binding affinity, bioavailability, pharmacokinetics and toxicity of the compounds, it is proposed that the NP T3 can act as a potential drug candidate against COVID-19 virus.

Identification of 4-acrylamido-N-(pyridazin-3-yl)benzamide as anti-COVID-19 compound: a DFTB, molecular docking, and molecular dynamics study.

Omicron is one of the variants of COVID-19 and continuing member of a pandemic. There are several types of vaccines that were developed around the globe to fight against the virus. However, the world is suffering to find suitable drug candidates for the virus. The main protease (Mpro) enzyme of the virus is the best target for finding drug molecules because of its involvement in viral infection and protein synthesis. ZINC-15 is a database of 750 million commercially available compounds. We find 125 compounds having two aromatic rings and amide groups for non-covalent interactions with active site amino acids and functional groups with the capability to bind -SH group of C145 of Mpro through covalent bonding by a nucleophilic addition reaction. The lead compound (Z144) was identified using molecular docking. The non-covalent interactions (NCI) calculations show the interactions between amino acids present in the active site of the protein and the lead molecules are attractive in nature. The density functional-based tight-binding (DFTB) study of the lead compound with amino acids in the active site indicates that Q190 and Q193 play a very critical role in stabilization. The Michael addition of the acrylamide group of the lead molecule at ß-position is facile because the low energy lowest unoccupied molecular orbital (LUMO) is concentrated on the group. From molecular dynamics during 100 ns, it has come to light that strong non-covalent interactions are key for the stability of the lead inside the protein and such binding can fold the protein. The free energy for this interaction is -42.72 kcal mol-1 which was obtained from MM-GB/SA calculations.

A crystallography-based investigation of weak interactions for drug design against COVID-19.

Interactions between proteins and small molecules play important roles in the inhibition of protein function. However, a lack of proper knowledge about non-covalent interactions can act as a barrier towards gaining a complete understanding of the factors that control these associations. To find effective molecules for COVID-19 inhibition, we have quantitatively investigated 143 X-ray crystal structures of the SARS-CoV-2 Mpro protein of coronavirus with covalently or non-covalently bound small molecules (SMs). Our present study is able to explain ordinary and perceptive aspects relating to protein inhibition. The active site of the protein consists of 21 amino acid residues, but only nine are actively involved in the ligand binding process. The H41, M49, and C145 residues have highest priority with respect to interactions with small molecules through hydrogen bond, CH-π, and van der Waals interactions. At the active site, this ranking of amino acids is clear, based on different spatial orientations of ligands, and consistent with the electronic properties. SMs with aromatic moieties that bind to the active site of the protein play a distinct role in the determination of the following order of interaction frequency with the amino acids: CH-π > H-bonding > polar interactions. This present study revealed that the G143 and C145 residues play crucial roles in the recognition of the carbonyl functionality of SMs through hydrogen bonding. With this knowledge in mind, an effective inhibitor small-molecule for SARS-CoV-2 Mpro was designed: docking studies showed that the designed molecule has strong binding affinity towards the protein. The non-covalent interactions in the protein-ligand complex are in good agreement with the results obtained from X-ray crystallography. Moreover, the present study focused on weak forces and their influence on protein inhibition, henceforth shedding much light on the essential requirements for moieties that should be present in a good inhibitor and their orientations at the ligand binding site.

Molecular designing, crystal structure determination and in silico screening of copper(II) complexes bearing 8-hydroxyquinoline derivatives as anti-COVID-19.

The pandemic by COVID-19 is hampering everything on the earth including physical and mental health, daily life and global economy. At the moment, there are no defined drugs, while few vaccines are available in the market to combat SARS-CoV-2. Several organic molecules were designed and tested against the virus but they did not show promising activity. In this work we designed two copper complexes from the ligands analogues with chloroquine and hydroxychloroquine. Both the ligands and complexes were well characterized by using various spectroscopic, thermal and X-ray diffraction techniques. Both the complexes as well as ligands were screened through in silico method with the chloroquine and hydroxychloroquine which essentially proved pivotal for successful understanding towards the target protein and their mechanism of action. The results indicated that the balanced hydrophobic and polar groups in the complexes favor their binding in the active site of the viral ADP-ribose-1 monophosphatase enzyme over the parent organic molecules.

In silico fight against novel coronavirus by finding chromone derivatives as inhibitor of coronavirus main proteases enzyme

Novel coronavirus, 2019-nCoV is a danger to the world and is spreading rapidly. Very little structural information about 2019-nCoV make this situation more difficult for drug designing. Benzylidenechromanones, naturally occurring oxygen heterocyclic compounds, having capability to inhibit various protein and receptors, have been designed here to block mutant variety of coronavirus main protease enzyme (SARC-CoV-2 M(pro)) isolated from 2019-nCoV with the assistance of molecular docking, bioinformatics and molecular electrostatic potential. (Z)-3-(4'-chlorobenzylidene)-thiochroman-4-one showed highest binding affinity to the protein. Binding of a compound to this protein actually inhibits the replication and transcription of the virus and, ultimately, stop the virus multiplication. Incorporation of any functional groups to the basic benzylidenechromanones enhances their binding ability. Chloro and bromo substitutions amplify the binding affinity. ADME studies of all these compounds indicate they are lipophilic, high gastro intestine absorbable and blood-brain barrier permeable. The outcome reveals that the investigated benzylidenechromanones can be examined in the case of 2019-nCoV as potent inhibitory drug of SARC-CoV-2 M(pro), for their strong inhibition ability, high reactivity and effective pharmacological properties.