LEADD: Lamarckian evolutionary algorithm for de novo drug design

Given an objective function that predicts key properties of a molecule, goal-directed de novo molecular design is a useful tool to identify molecules that maximize or minimize said objective function. Nonetheless, a common drawback of these methods is that they tend to design synthetically unfeasible molecules. In this paper we describe a Lamarckian evolutionary algorithm for de novo drug design (LEADD). LEADD attempts to strike a balance between optimization power, synthetic accessibility of designed molecules and computational efficiency. To increase the likelihood of designing synthetically accessible molecules, LEADD represents molecules as graphs of molecular fragments, and limits the bonds that can be formed between them through knowledge-based pairwise atom type compatibility rules. A reference library of drug-like molecules is used to extract fragments, fragment preferences and compatibility rules. A novel set of genetic operators that enforce these rules in a computationally efficient manner is presented. To sample chemical space more efficiently we also explore a Lamarckian evolutionary mechanism that adapts the reproductive behavior of molecules. LEADD has been compared to both standard virtual screening and a comparable evolutionary algorithm using a standardized benchmark suite and was shown to be able to identify fitter molecules more efficiently. Moreover, the designed molecules are predicted to be easier to synthesize than those designed by other evolutionary algorithms. Graphical Abstract

Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases

SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.

Computer-Aided Drug Design (CADD) to De-Orphanize Marine Molecules: Finding Potential Therapeutic Agents for Neurodegenerative and Cardiovascular Diseases

Computer-aided drug design (CADD) techniques allow the identification of compounds capable of modulating protein functions in pathogenesis-related pathways, which is a promising line on drug discovery. Marine natural products (MNPs) are considered a rich source of bioactive compounds, as the oceans are home to much of the planet’s biodiversity. Biodiversity is directly related to chemodiversity, which can inspire new drug discoveries. Therefore, natural products (NPs) in general, and MNPs in particular, have been used for decades as a source of inspiration for the design of new drugs. However, NPs present both opportunities and challenges. These difficulties can be technical, such as the need to dive or trawl to collect the organisms possessing the compounds, or biological, due to their particular marine habitats and the fact that they can be uncultivable in the laboratory. For all these difficulties, the contributions of CADD can play a very relevant role in simplifying their study, since, for example, no biological sample is needed to carry out an in-silico analysis. Therefore, the amount of natural product that needs to be used in the entire preclinical and clinical study is significantly reduced. Here, we exemplify how this combination between CADD and MNPs can help unlock their therapeutic potential. In this study, using a set of marine invertebrate molecules, we elucidate their possible molecular targets and associated therapeutic potential, establishing a pipeline that can be replicated in future studies.

Molecules Containing Cyclobutyl Fragments as Therapeutic Tools: A Review on Cyclobutyl Drugs

In recent years, cyclobutyl has become ever more influential in the field of drug design. Its unique four-membered ring structure is not only a useful intermediate for the synthesis of biomedical candidate materials, but also an indispensable framework for drug design and application. According to the therapeutic field, cyclobutyl drugs are roughly divided into tumor and cancer drugs, nervous system drugs, analgesics, antiviral drugs, and gastrointestinal drugs. Among them, platinum-based anticancer drugs containing cyclobutyl fragments have achieved remarkable success in the treatment of cancer, bringing new hope for the development of more cyclobutyl drugs. This article provides details of the research progress of the structure types, structure-activity relationships, targets, and mechanisms of cyclobutyl drugs that have been on the market or are in the clinical stage, and provides ideas for the discovery and synthesis of novel cyclobutyl-containing drugs.

Fragment based drug design

Rational approaches towards drug development have emerged as one of the most promising ways among the tedious conventional procedures with the aim of redefining the drug discovery process. The need of current medical system is demanding a much precise, faster and reliable approaches in parallel to faster growing technology for development of drugs with more intrinsic action and fewer side effects. Systematic and well-defined diagnostic studies have revealed the specific causes of disease and related targets for drug development. Designing a drug as per the specific target, studying it in-silico prior to its development has been proved as an added benefit to the studies. Many approaches like structure based drug design, fragment based drug design and ligand based drug design are been in practice for the drug discovery and development with the similar fundamental theory. Fragment based drug design utilizes a library of fragments designed specifically for the concerned target and these fragments are studied further before screening with virtual methods as well as with biophysical methods. The process follows a well-defined pathway which moulds a fragment into a perfect drug candidate. In this chapter we have tried to cover all the basic aspects of fragment based drug design and related technologies.

An overview of in silico methods used in the design of VEGFR-2 inhibitors as anticancer agents

VEGFR-2 enzyme known for physiological functioning of the cell also involves in pathological angiogenesis and tumor progression. Recently VEGFR-2 has gained the interest of researchers all around the world as a promising target for the drug design and discovery of new anticancer agents. VEGFR2 inhibitors are a major class of anticancer agents used for clinical purposes. In silico methods like virtual screening, molecular docking, molecular dynamics, pharmacophore modeling, and other computational approaches help extensively in identifying the main molecular interactions necessary for the binding of the small molecules with the respective protein target to obtain the expected pharmacological potency. In this chapter, we discussed some representative case studies of in silico techniques used to determine molecular interactions and rational drug design of VEGFR-2 inhibitors as anticancer agents.