Gefitinib derivatives and drug-resistance: A perspective from molecular dynamics simulations.

Epidermal-growth factor receptor (EGFR) is a transmembrane tyrosine kinase (TK) with a significant role in cell survival. EGFR is upregulated in various cancer cells and known as a druggable target. Gefitinib is a first-line TK inhibitor used against metastatic non-small cell lung cancer (NSCLC). Despite initial clinical response, a conserved therapeutic effect could not be achieved due to the occurrence of resistance mechanisms. Point mutations in EGFR genes are one of the major causes of rendered tumor sensitivity. To aid in the development of more efficient TKIs, chemical structures of prevailing drugs and their target binding patterns are very important. The aim of the present study was to propose synthetically-accessible gefitinib congeners with enhanced binding fitness to clinically frequent EGFR mutants. Docking simulations of intended molecules identified 1-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-3-(oxazolidin-2-ylmethyl) thiourea (23) as a top-binder structure inside G719S, T790 M, L858R and T790 M/L858R-EGFR active sites. Superior docked complexes were subjected to the entire 400 ns molecular dynamics (MD) simulations. Analysis of data revealed the stability of mutant enzymes upon binding to molecule 23. All mutant complexes with the exception of a T790 M/L858R-EGFR, were majorly stabilized through cooperative hydrophobic contacts. Pairwise analysis of H-bonds proved Met793 as the conserved residue with stable H-bond participations as hydrogen bond donor (Frequency 63-96%). Amino acid decomposition analysis confirmed the probable role of Met793 in complex stabilization. Estimated binding free energies indicated the proper accommodation of molecule 23 inside target active sites. Pairwise energy decompositions of stable binding modes revealed the energetic contribution of key residues. Although wet lab experiments are required to unravel the mechanistic details of mEGFR inhibition, MD results provide structural basis for those events that are difficult to address experimentally. The outputs of the current study may assist to design small molecules with high potency to mEGFRs.

Current Status and Structure Activity Relationship of Privileged Azoles as Antifungal Agents (2016-2020).

Fungal infections have greatly contributed to infectious-related deaths in the past century. This issue has become worse with the advent of immunity-impairing conditions such as HIV. The eukaryote nature of fungal pathogens makes them harder to eradicate than bacterial infections. Given the importance of the problem, considerable efforts have been made to the synthesis and biological assessment of azole-based chemical scaffolds and their bioisosteres. The emergence of validated macromolecular targets within different fungal species has inspired structure-based drug design strategies toward diverse azole-based agents. Despite advantageous features, the emergence of drug-resistant fungal species has restricted the applicability of current azoles as first-line antifungal agents. Consequently, it appears advisable to elucidate the structure activity relationships (SAR) and chemical biodiversity within antifungal azoles. This review is devoted to a brief look at clinically applied drugs, structure-based classification of azole antifungals and their SAR. The reviewed molecules belong to the antifungal structures that were reported throughout 2016-2020.