Scaffold hopping approaches for dual-target antitumor drug discovery: opportunities and challenges.

INTRODUCTION: Scaffold hopping has emerged as a practical tactic to enrich the synthetic bank of small molecule antitumor agents. Specifically, it enables the chemist to refine the lead compound's pharmacodynamic, pharmacokinetic, and physiochemical properties. Scaffold hopping opens up fresh molecular territory beyond established patented chemical domains. AREA COVERED: The authors present the scaffold hopping-based drug design strategies for dual inhibitory antitumor structural templates in this review. Minor modifications, structure rigidification and simplification (ring-closing and opening), and complete structural overhauls were the strategies employed by the medicinal chemist to generate a library of bifunctional inhibitors. In addition, the review presents an overview of the computational methods of scaffold hopping (software and programs) and organopalladium catalysis leveraged for the synthesis of templates designed via scaffold hopping. EXPERT OPINION: The medicinal chemist has demonstrated remarkable prowess in furnishing dual inhibitory antitumor chemical architectures. Scaffold hopping-based drug design strategies have yielded a plethora of pharmacodynamically superior dual modulatory antitumor agents. An integrated approach involving computational advancements, synthetic methodology advancements, and conventional drug design strategies is required to increase the number of scaffold-hopping-assisted drug discovery campaigns.

New sulphonamide-peptide hybrid molecules as potential PBP 2a ligands and methicillin resistant Staphylococcus aureus actives.

Penicillin binding protein 2a (PbP 2a) expression accounts for the insusceptibility of methicillin-resistant Staphylocuccus aureus (MRSA) to ß-lactam antibiotics. Here we employed computational strategies to challenge PbP 2a with series of fifty-five 'ala-ala' and 'ala-pro' sulphonamide-dipeptides. Binding stability of two compounds (labeled: 10i and 10n) with theoretical Ki in nM and µM ranges, for PbP 2a active and allosteric sites respectively, were investigated using molecular dynamics simulations. In addition, the results of the sensitivity of four strains of MRSA for compounds 10i and 10n obtained revealed the compounds at 10 µg/ml caused two isolates (S4 and S10) to revert to being susceptible. Finally, a reliable binding conformations of both compounds in the two binding sites of PbP 2a are described to provide rationale for structure-activity optimization of this series.Communicated by Ramaswamy H. Sarma.

Computational Applications in Secondary Metabolite Discovery (CAiSMD): an online workshop.

We report the major conclusions of the online open-access workshop "Computational Applications in Secondary Metabolite Discovery (CAiSMD)" that took place from 08 to 10 March 2021. Invited speakers from academia and industry and about 200 registered participants from five continents (Africa, Asia, Europe, South America, and North America) took part in the workshop. The workshop highlighted the potential applications of computational methodologies in the search for secondary metabolites (SMs) or natural products (NPs) as potential drugs and drug leads. During 3 days, the participants of this online workshop received an overview of modern computer-based approaches for exploring NP discovery in the "omics" age. The invited experts gave keynote lectures, trained participants in hands-on sessions, and held round table discussions. This was followed by oral presentations with much interaction between the speakers and the audience. Selected applicants (early-career scientists) were offered the opportunity to give oral presentations (15 min) and present posters in the form of flash presentations (5 min) upon submission of an abstract. The final program available on the workshop website ( https://caismd.indiayouth.info/ ) comprised of 4 keynote lectures (KLs), 12 oral presentations (OPs), 2 round table discussions (RTDs), and 5 hands-on sessions (HSs). This meeting report also references internet resources for computational biology in the area of secondary metabolites that are of use outside of the workshop areas and will constitute a long-term valuable source for the community. The workshop concluded with an online survey form to be completed by speakers and participants for the goal of improving any subsequent editions.