Identification of EGFR inhibitors as potential agents for cancer therapy: pharmacophore-based modeling, molecular docking, and molecular dynamics investigations.

CONTEXT: As a member of a large family of proteins that together regulate various aspects of cell growth and development, the epidermal growth factor receptor (EGFR) is a validated target for the development of new drugs. Herein, we compiled a library of 62 compounds from the PubChem database with similar pharmacophores as osimertinib, which to our knowledge represents the only drug capable of overcoming EGFR-T790M-mutated NSCLC until date. Subsequently, we launched a docking-based virtual screening campaign against the EGFR kinase with the compiled chemical entities. The virtual screen identified 3 hit candidates (CID_126667097, CID_137660592, and CID_137659061) with lower binding energy/higher affinity (- 8.7 kcal/mol, - 8.6 kcal/mol, and - 8.5 kcal/mol, respectively) than the standard osimertinib (- 8.4 kcal/mol). Molecular dynamics metrics such as RMSD, RMSF, ROG, and intermolecular H-bond were used to substantiate the stability of the promising drug candidates at the binding pocket of EGFR after 100,000 ps production run. Overall, our molecular modeling study portrayed CID_126667097, CID_137660592, and CID_137659061 as lead-like drug candidates that may be further developed for the treatment of EGFR-associated cancer disease. METHODS: Molecular docking was conducted with Autodock Vina. A total of 62 compounds were compiled for the docking screen, which were then downloaded in SMILE format and converted to Protein Data Bank (PDB) format using the Openbabel online server. Finally, Gromacs 2022.3 was used to perform MD simulation to substantiate the stability of the hit candidates.

Promising disruptors of p53-MDM2 dimerization from some medicinal plant phytochemicals: a molecular modeling study.

Cancer is a major global health issue that has a high mortality rate. p53, which functions as a tumor suppressor, is critical in preventing tumor development by regulating the cell cycle and inducing apoptosis in damaged cells. However, the tumor suppressor function of p53 is effectively inhibited by its direct interaction with the hydrophobic cleft of MDM2 protein via multiple mechanisms As a result, restoring p53 activity by blocking the p53-MDM2 protein-protein interaction has been proposed as a compelling therapeutic strategy for cancer treatment. The use of molecular docking and phytochemical screening procedures are appraised to inhibit MDM2's hydrophobic cleft and disrupt the p53-MDM2 interaction. For this purpose, a library of 51 bioactive compounds from 10 medicinal plants was compiled and subjected to structure-based virtual screening. Out of these, only 3 compounds (Atalantoflavone, Cudraxanthone 1, and Ursolic acid) emerged as promising inhibitors of MDM2-p53 based on their binding affinities (-9.1 kcal/mol, -8.8 kcal/mol, and -8.8 kcal/mol respectively) when compared to the standard (-8.8 kcal/mol). Moreover, these compounds showed better pharmacokinetic and drug-like profiling than the standard inhibitor (Chromonotriazolopyrimidine 1). Finally, the 100 ns MD simulation analysis confirmed no significant perturbation in the conformational dynamics of the simulated binary complexes when compared to the standard. In particular, Ursolic acid was found to satisfy the molecular enumeration the most compared to the other inhibitors. Our overall molecular modeling finding shows why these compounds may emerge as potent arsenals for cancer therapeutics. Nonetheless, extensive experimental and clinical research is needed to augment their use in clinics.Communicated by Ramaswamy H. Sarma.

Bioinformatics analysis of structural protein to approach a vaccine candidate against Vibrio cholerae infection.

The bacteria Vibrio cholerae causes cholera, an acute diarrheal infection that can lead to dehydration and even death. Over 100,000 people die each year as a result of epidemic diseases; vaccination has emerged as a successful strategy for combating cholera. This study uses bioinformatics tools to create a multi-epitope vaccine against cholera infection using five structural polyproteins from the V. cholerae (CTB, TCPA, TCPF, OMPU, and OMPW). The antigenic retrieved protein sequence were analyzed using BCPred and IEDB bioinformatics tools to predict B cell and T cell epitopes, respectively, which were then linked with flexible linkers together with an adjuvant to boost it immunogenicity. The construct has a theoretical PI of 6.09, a molecular weight of 53.85 kDa, and an estimated half-life for mammalian reticulocytes in vitro of 4.4 h. These results demonstrate the construct's longevity. The vaccine design was docked against the human toll-like receptor (TLR) to evaluate compatibility and effectiveness; also other additional post-vaccination assessments were carried out on the designed vaccine. Through in silico cloning, its expression was determined. The results show that it has a CAI value of 0.1 and GC contents of 58.97% which established the adequate expression and downstream processing of the vaccine construct, and our research demonstrated that the multi-epitope subunit vaccine exhibits antigenic characteristics. Additionally, we carried out an in silico immunological simulation to examine the immune reaction to an injection. Our results strongly suggest that the vaccine candidate on further validation would induce immune response against the V. cholerae infection.

Integrated virtual screening and molecular dynamics simulation revealed promising drug candidates of p53-MDM2 interaction.

In the vast majority of malignancies, the p53 tumor suppressor pathway is compromised. In some cancer cells, high levels of MDM2 polyubiquitinate p53 and mark it for destruction, thereby leading to a corresponding downregulation of the protein. MDM2 interacts with p53 via its hydrophobic pocket, and chemical entities that block the dimerization of the protein-protein complex can restore p53 activity. Thus far, only a few chemical compounds have been reported as potent arsenals against p53-MDM2. The Protein Data Bank has crystallogaphic structures of MDM2 in complex with certain compounds. Herein, we have exploited one of the complexes in the identification of new p53-MDM2 antagonists using a hierarchical virtual screening technique. The initial stage was to compile a targeted library of structurally appropriate compounds related to a known effective inhibitor, Nutlin 2, from the PubChem database. The identified 57 compounds were subjected to virtual screening using molecular docking to discover inhibitors with high binding affinity for MDM2. Consequently, five compounds with higher binding affinity than the standard emerged as the most promising therapeutic candidates. When compared to Nutlin 2, four of the drug candidates (CID_140017825, CID_69844501, CID_22721108, and CID_22720965) demonstrated satisfactory pharmacokinetic and pharmacodynamic profiles. Finally, MD simulation of the dynamic behavior of lead-protein complexes reveals the stability of the complexes after a 100,000 ps simulation period. In particular, when compared to the other three leads, overall computational modeling found CID_140017825 to be the best pharmacological candidate. Following thorough experimental trials, it may emerge as a promising chemical entity for cancer therapy.