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The discovery of new pharmaceuticals via computer modeling is one of the key challenges in modern medicine. The advent of global networks of genomic, proteomic and metabolomic endeavors is ushering in an increasing number of novel and clinically important targets for screening. Computational methods are anticipated to play a pivotal role in exploiting the structural and functional information to understand specific molecular recognition events of the target macromolecule with candidate hits leading ultimately to the design of improved leads for the target. In this review, we sketch a system independent, comprehensive physicochemical pathway for lead molecule design focusing on the emerging in silico trends and techniques. We survey strategies for the generation of candidate molecules, docking them with the target and ranking them based on binding affinities. We present a molecular level treatment for distinguishing affinity from specificity of a ligand for a given target. We also discuss the significant aspects of drug absorption, distribution, metabolism, excretion and toxicity (ADMET) and highlight improved protocols required for higher quality and throughput of in silico methods employed at early stages of discovery. We present a realization of the various stages in the pathway proposed with select examples from the literature and from our own research to demonstrate the way in which an iterative process of computer design and validation can aid in developing potent leads. The review thus summarizes recent advances and presents a viewpoint on improvements envisioned in the years to come for automated computer aided lead molecule discovery.

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Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized by chronic inflammation and destruction of multiple small joints which may lead to systemic complications. Altered immunity via pathogenic autoantibodies pre-date clinical symptom development by several years. Incompletely understood range of mechanisms trigger joint-homing, leading to clinically evident articular disease. Advances in therapeutic approaches and understanding pathogenesis have improved prognosis and likely remission. However, partial/non-response to conventional and biologic therapies witnessed in a subset of patients highlights the need for new therapeutics. It is now evident that joint disease chronicity stems from recalcitrant inflammatory synovial environment, majorly maintained by epigenetically and metabolically reprogrammed synoviocytes. Therefore, interference with effector functions of activated cell types seems a rational strategy to reinstate synovial homeostasis and complement existing anti-inflammatory interventions to mitigate chronic RA. Presenting this newer aspect of fibroblast-like synoviocytes and myeloid cells underlying the altered synovial biology in RA and its potential for identification of new druggable targets is attempted in this review. Major leads from i) molecular insights of pathogenic cell types from hypothesis free OMICS approaches; ii) hierarchy of their dysregulated signaling pathways; and iii) knowledge of druggability of molecular nodes in these pathways are highlighted. Development of such synovial biology-directed therapeutics hold promise for an enriched drug repertoire for RA.